Design, synthesis and anticancer activity of ß-carboline based pseudo-natural products by inhibiting AKT/mTOR signaling pathway.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer deaths. Much progress has been made to treat NSCLC, however, only limited patients can benefit from current treatments. Thus, more efforts are needed to pursue novel molecular modalities for NSCLC treatment. It was demonstrated that pseudo-natural products (PNP) are a critical source for antitumor drug discovery. Herein, we describe a CH activation protocol for the expedient construction of a focused library utilizing the PNP rational design strategy. This protocol features a rhodium-catalyzed CH activation/ [4+2] annulation reaction between N-OAc-indole-2-carboxamide and alkynyl quinols, enabling facile access to diverse quinol substituted ß-carboline derivatives (31 examples). The anticancer activities were assessed in vitro against NSCLC cell line A549, yielding a potent antiproliferative ß-carboline derivative (8r) with an IC50 value of 0.8 ± 0.1 µM. Further investigation revealed that this compound could decrease the expression of Caspase 3, and increase the expression of autophagic protein Cyclin B1, thus markedly inducing autophagy and apoptosis. Mechanistic study suggested that 8r could be a potent anti-NSCLC agent through the AKT/mTOR signaling pathway in A549 cells. Moreover, the anticancer activities were also assessed against three other cancer cell lines, and 8r exhibits a broader inhibitory effect on cell proliferation in all cancer cell lines tested. These results indicated that carboline-based PNPs show great potential to induce cell autophagy and apoptosis, which serve as good leads for further drug discovery.

Visualization analysis of research frontiers and trends in the treatment of sciatic nerve injury.

Objective: To visualize and analyze the literature related to sciatic nerve injury treatment from January 2019 to December 2023, and summarize the current status, hotspots, and development trends of research in this field. Methods: Using CiteSpace and VOSviewer software, we searched the Web of Science database for literature related to the treatment of sciatic nerve injury. Then we analyzed and plotted visualization maps to show the number of publications, countries, institutions, authors, keywords, references, and journals. Results: A total of 2,653 articles were included in the English database. The annual number of publications exceeded 230, and the citation frequency increased yearly. The United States and China were identified as high-influence nations in this field. Nantong University was the leading institution in terms of close cooperation among institutions. The authors Wang Yu had the highest number of publications and were highly influential in this field. Keyword analysis and reference Burst revealed a research focus on nerve regeneration and neuropathic pain, which involve regenerative medicine and neural tissue engineering. Chronic pain resulting from sciatic nerve injury often manifests alongside anxiety, depression, cognitive-behavioral disorders, and other issues. Interventions such as stem cells, electrical stimulation, electroacupuncture, total joint replacement, pharmacological interventions, gene therapy, nerve conduits, chitosan scaffolds, and exercise promote nerve repair and alleviate pain. Schwann cells have been the focus of much attention in nerve repair and regeneration. Improving the outcome of sciatic nerve injury is a current research challenge and focus in this field. Based on keyword Burst, nerve conduits and grafts may become a potential research hotspot in the treatment of sciatic nerve injury. Conclusion: This visual analysis summarizes research trends and developments of sciatic nerve injury treatment and predicts potential research frontiers and hot directions.

[4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

Advancing vaccine development: Evaluation of a mannose-modified lipid nanoparticle-based candidate for African swine fever p30 mRNA vaccine eliciting robust immune response in mice.

The African swine fever virus (ASFV) continues to pose significant economic and pandemic risks. Consequently, discovering new, efficient vaccines is crucial. Messenger RNA (mRNA) vaccines have emerged as promising candidates, providing minimal risk of insertional mutagenesis, high safety profiles, effectiveness, rapid scalability in production, and cost-effectiveness. In this study, we have developed an ASF p30 mRNA vaccine candidate (mRNA/Man-LNP) employing mannose-modified lipid nanoparticles (LNPs). The mRNA/Man-LNP exhibited effective antigen presentation and facilitated dendritic cells (DCs) maturation. Notably, it elicited strong IgG titers and activated CD4+ and CD8+ T-cells in immunized mice, all while adhering to stringent biosafety standards. This investigation demonstrates that mRNA/Man-LNP can trigger both humoral and cellular immune responses, suggesting its potential as a potent and promising vaccine candidate for controlling African swine fever (ASF).

Taishania pollutisoli gen. nov., sp. nov., Isolated from Tetrabromobisphenol A-Contaminated Soil.

Strain CZZ-1T was isolated from long-term TBBPA-contaminated soil Zaozhuang city, Shandong province, People's Republic of China. CZZ-1T was pink-pigmented, Gram-stain-negative, rod-shaped, non-motile and aerobic. The 16S rRNA gene analysis indicated that strain CZZ-1T shows high similarities to Fluviicola taffensis DSM 16823T (92.6%) and Fluviicola hefeinensis KACC 16597T (92.5%) and less than 91% sequence similarities to other genus or species in the family Crocinitomicaceae. It was able to grow at 10-37 °C, with 0-6% (w/v) NaCl. It could hydrolyze gelatin, but could not reduce nitrates to nitrites. The predominant fatty acids of strain CZZ-1T were iso-C15:0 (51.3%), C15:0 2-OH (11.0%), iso-C17:0 3-OH (8.0%), C14: 0 (7.0%), iso-C15:1 G (6.8%) and Summed Feature 3 (C16:1 ω7c and/or C16:1 ω6c, 4.4%). The polar lipid profile was composed of five unidentified lipids, two unidentified phospholipids, one phosphatidylethanolamine, one unidentified aminolipid and one unidentified glycolipid. The predominant respiratory quinone was MK-6. The genomic DNA G+C content of strain CZZ-1T was 41.5 mol%. Based on data from phenotypic, chemotaxonomic and genotypic analysis in this study, strain CZZ-1T represents a novel species in a new genus in the family Crocinitomicaceae, for which the name Taishania pollutisoli gen. nov., sp. nov. is proposed. The type strain is CZZ-1T (= KCTC 52343T = GDMCC 1.2270T).

A network meta-analysis for efficacies and toxicities of different therapeutic regimens in the treatment of advanced nasopharyngeal carcinoma.

PURPOSE: The current study set out to compare the efficacies and toxicities (grad 3 and 4) between concurrent chemoradiotherapy (CCRT), induction chemotherapy plus radiotherapy (IC + RT), IC + CCRT, RT and CCRT + adjuvant chemotherapy (CCRT + AC) in regard to advanced nasopharyngeal carcinoma (NPC) treatment using a network meta-analysis. METHODS: Literature retrieval was conducted using PubMed, Cochrane Library and other English databases. Eligible randomized controlled trails (RCTs) of 5 different regimens were included. The network meta-analysis combined direct and indirect comparisons to measure pooled odd ratios (OR) and the surface under the cumulative ranking curves (SUCRA). RESULTS: A total of eight eligible RCTs were enrolled into this network meta-analysis after initial exclusion. With respect to hematologic toxicity, CCRT + AC exhibited higher toxicity in patients with advanced NPC in terms of anemia and leukopenia/neutropenia compared to RT. As for anemia, the toxicity of IC + CCRT was higher than those with advanced NPC. In addition, CCRT exhibited higher toxicity than RT in relation to leukopenia/neutropenia. Non-hematologic toxicity in regard to nausea/vomiting suggested that CCRT, IC + CCRT and CCRT + AC presented with higher levels of toxicity in patients with advanced NPC, in contrast to RT. Lastly, RT was found to be less toxic but with higher five-year overall survival (OS) rate in patients with advanced NPC, while CCRT, IC + CCRT and CCRT + AC were more toxic in patients with advanced NPC. CONCLUSION: Among the five therapeutic regimens, the survival rate of IC + RT was similar to that of CCRT, and the toxicity SUCRA value of IC + RT was lower than that of CCRT. Together, our findings indicate that IC + RT may be a potentially acceptable treatment alternative to CCRT for advanced NPC, and is worthy of further investigation.

Botulinum Toxin Type A Possibly Affects Cav3.2 Calcium Channel Subunit in Rats with Spinal Cord Injury-Induced Muscle Spasticity.

INTRODUCTION: Spinal cord injury (SCI) often causes muscle spasticity, which can be inhibited by using calcium channel blocker. Botulinum toxin type A (BoT-A) shows therapeutic efficacy on spasticity and may exert inhibitory effects on the calcium channel. METHODS: A rat model with muscle spasticity was established after SCI via contusion and compression. Different concentrations (0, 1, 3 and 6 U/kg) of BoT-A Botox were injected in the extensor digitorum longus (EDL) muscles of the right hindlimb in the muscle spasticity model. The changes of muscle spasticity and calcium level in EDL muscles were measured after the establishment of SCI-induced spasticity. Cav3.2 calcium channel subunit and its mutant (M1560V) were analyzed using Western blot before (input) or after immunoprecipitation with anti-FLAG antibody, and their currents were measured in motoneurons by using whole-cell voltage clamp recordings. RESULTS: SCI induced muscle spasticity, whereas calcium level in EDL muscles and expression of Cav3.2 was increased in the SCI model when compared with the sham group (p < 0.05). BoT-A Botox treatment significantly reduced muscle spasticity and calcium level in EDL muscles and Cav3.2 expression in a dose-dependent way (p < 0.05). The ratio of biotinylated to total Cav3.2 was reduced in the mutant (M1560V) of Cav3.2 and lower than that in the wild Cav3.2. BoT-A Botox intervention also reduced the current values of calcium channel and the ratio in a dose-dependent way (p < 0.05). DISCUSSION: BoT-A Botox possibly attenuates SCI-induced muscle spasticity by affecting the expression of Cav3.2 calcium channel subunit in the rat models. There may be multiple mechanisms for the function of BoT-A Botox. Further work is needed to be done to address these issues.

Brain-targeted co-delivery of ß-amyloid converting enzyme 1 shRNA and epigallocatechin-3-gallate by multifunctional nanocarriers for Alzheimer's disease treatment.

Progressive memory loss and cognitive dysfunction are hallmark clinical features of Alzheimer's disease (AD). As a possible treatment for AD, we developed an epigallocatechin-3-gallate (EGCG) and ß-site amyloid precursor protein (APP) cleaving enzyme 1 antisense (BACE1-AS) shRNA-encoded plasmid. The plasmid was loaded on to RVG29 peptide-targeted multifunctional nanoparticles (NPs) (REGS-PN). The polymeric NPs were characterized by flow cytometry, biocompatibility assay, pharmacokinetic analysis, Western blot analysis, and the Morris water maze (MWM) test. The differences in plasma and brain NP accumulation following intravenous administration showed a significantly longer circulation time for EGS-PN and REGS-PN in the blood stream. In contrast, free EGCG was rapidly eliminated from the circulation. REGS-PM successfully travelled through the blood-brain barrier and was present at a higher concentration in the brain compared with both non-targeted NPs and free EGCG. REGS-PN administration to APPswe/PS1dE9 double transgenic mice (APP/PS1 mice) resulted in downregulation of the key enzyme in amyloid-ß formation (BACE1) and amyloid beta, indicating synergistic therapeutic activity. The MWM test revealed that simultaneous delivery of a therapeutic gene and EGCG (REGS-PN) remarkably improved the spatial learning and memory capabilities of APP/PS1 mice as well as wild type mice compared with the free EGCG-treated group. With these results, we propose that co-delivery of a therapeutic gene (shRNA) and EGCG in a multifunctional nanocarrier could achieve higher therapeutic concentrations in the brain and could be an excellent strategy for AD treatment.

Phytoremediation of acetochlor residue by transgenic Arabidopsis expressing the acetochlor N-dealkylase from Sphingomonas wittichii DC-6.

Transgenic engineering is an effective way for plants to obtain strong degradation or detoxification abilities to target pollutants. Acetochlor is an important and widely used herbicide, however, its residue is persistent in soil and is toxic to humans and rotation crops. In this study, the degradation ability and tolerance to acetochlor of transgenic Arabidopsis thaliana synthesizing the oxygenase component, CndA, of the bacterial acetochlor N-dealkylase system, CndABC, were investigated. Two transgenic plants, including a cytoplasm transformant, in which the CndA was located in the cytoplasm, and a chloroplast transformant, in which the CndA was located in the chloroplast, were constructed. The cytoplasm transformant acquired only weak acetochlor degradation activity and displayed little acetochlor tolerance. In contrast, the chloroplast transformant exhibited high degradation efficiency and strong tolerance to acetochlor; it could transform 94.3% of 20 µM acetochlor in water within 48 h and eliminate 80.2% of 5 mg/kg acetochlor in soil within 30 d. The metabolite of acetochlor N-dealkylation catalyzed by CndA, 2-chloro-N-(2-methyl-6-ethylphenyl)acetamide (CMEPA), could be released outside the cells by chloroplast transformant and further degraded by indigenous microorganisms in the soil. This study provides an effective strategy for the phytoremediation of acetochlor residue in water and soil.

A Multilevel Analysis of Job Characteristics, Emotion Regulation, and Teacher Well-Being: A Job Demands-Resources Model.

This study integrated personal factors into the job demands-resources (JD-R) model to examine school- and individual-level predictors of teacher well-being. Survey data were gathered from 1,656 teachers from 54 schools. The results of hierarchical linear modeling indicated that the school-level emotional job demands of teaching and suppression at the individual level were positively related to teachers' anxiety and depression whereas school-level trust in colleagues and individual-level reappraisal were positively associated with enthusiasm and contentment. Positive relationship between emotional job demands and suppression was also found. These findings support the claim that reappraisal should be considered a personal resource and suppression a personal demand.