Advances in the use of local anesthetic extended-release systems in pain management.

Pain management remains among the most common and largely unmet clinical problems today. Local anesthetics play an indispensable role in pain management. The main limitation of traditional local anesthetics is the limited duration of a single injection. To address this problem, catheters are often placed or combined with other drugs in clinical practice to increase the time that local anesthetics act. However, this method does not meet the needs of clinical analgesics. Therefore, many researchers have worked to develop local anesthetic extended-release types that can be administered in a single dose. In recent years, drug extended-release systems have emerged dramatically due to their long duration and efficacy, providing more possibilities for the application of local anesthetics. This paper summarizes the types of local anesthetic drug delivery systems and their clinical applications, discusses them in the context of relevant studies on local anesthetics, and provides a summary and outlook on the development of local anesthetic extended-release agents.

Maternal vitamin D-related metabolome and offspring risk of asthma outcomes.

BACKGROUND: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. OBJECTIVE: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. METHODS: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC2010, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. RESULTS: In COPSAC2010, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmic sphingolipid level (P < .01). CONCLUSIONS: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.

Molecular insights into the chemodiversity of dissolved organic matter and its interactions with the microbial community in eco-engineered bauxite residue.

Dissolved organic matter (DOM) plays an important role in the biogeochemical function development of bauxite residue. Nevertheless, the DOM composition at the molecular level and its interaction with microbial community during soil formation of bauxite residue driven by eco-engineering strategies are still relatively unknown. In the present study, the DOM composition at the molecular level and its interactions with the microbial community in amended and revegetated bauxite residue were explored. The results showed that the amendment applications and revegetation enhanced the accumulation of unsaturated molecules with high values of double bond equivalent (DBE) and nominal oxidation of carbon (NOSC) and aromatic compounds with high values of modified aromaticity index (AImod) as well as the reduction of average weighted molecular mass of DOM molecules. Significant correlations between DOM molecules and the microbial community and Fe/Al oxides were found. DOM molecules were decomposed by the microbial community and sequestered onto Fe/Al oxides, which were the main driving factors that changed DOM chemodiversity in the amended and revegetated bauxite residue. These findings are beneficial for understanding the biogeochemical behaviours of DOM and providing a critical basis for the development of eco-engineering strategies towards soil formation and the sustainable revegetation of bauxite residue.

Attenuation of Yersinia pestis fyuA Mutants Caused by Iron Uptake Inhibition and Decreased Survivability in Macrophages.

Yersinia pestis is the etiological agent of plague, a deadly infectious disease that has caused millions of deaths throughout history. Obtaining iron from the host is very important for bacterial pathogenicity. Y. pestis possesses many iron uptake systems. Yersiniabactin (Ybt) plays a major role in iron uptake in vivo and in vitro, and in virulence toward mice as well. FyuA, a ß-barrel TonB-dependent outer membrane protein, serves as the receptor for Ybt. In this study, we examined the role of the fyuA gene in Y. pestis virulence using different challenging ways and explored the underlying mechanisms. The BALB/c mouse infection assay showed that the virulence of the mutant strains (ΔfyuA and ΔfyuAGCAdel) was lower when compared with that of the wild-type (WT) strain 201. Furthermore, the attenuation of virulence of the mutant strains via subcutaneous and intraperitoneal challenges was far greater than that via intravenous injection. Iron supplementation restored lethality during subcutaneous challenge with the two mutants. Thus, we speculated that the attenuated virulence of the mutant strains toward the mice may be caused by dysfunctional iron uptake. Moreover, ΔfyuA and ΔfyuAGCAdel strains exhibited lower survival rates in murine RAW264.7 macrophages, which might be another reason for the attenuation. We further explored the transcriptomic differences between the WT and mutant strains at different temperatures and found that the expressions of genes related to Ybt synthesis and its regulation were significantly downregulated in the mutant strains. This finding indicates that fyuA might exert a regulatory effect on Ybt. Additionally, the expressions of the components of the type III secretion system were unexpectedly upregulated in the mutants, which is inconsistent with the conventional view that the upregulation of the virulence genes enhances the virulence of the pathogens.

Integrative Analysis of Metabolomics and Transcriptomics Reveals Molecular Mechanisms of Anthocyanin Metabolism in the Zikui Tea Plant (Camellia sinensis cv. Zikui).

In this study, we performed an association analysis of metabolomics and transcriptomics to reveal the anthocyanin biosynthesis mechanism in a new purple-leaf tea cultivar Zikui (Camellia sinensis cv. Zikui) (ZK). Three glycosylated anthocyanins were identified, including petunidin 3-O-glucoside, cyanidin 3-O-galactoside, and cyanidin 3-O-glucoside, and their contents were the highest in ZK leaves at 15 days. This is the first report on petunidin 3-O-glucoside in purple-leaf tea. Integrated analysis of the transcriptome and metabolome identified eleven dependent transcription factors, among which CsMYB90 had strong correlations with petunidin 3-O-glucoside, cyanidin 3-O-galactoside, and cyanidin 3-O-glucoside (PCC > 0.8). Furthermore, we also identified key correlated structural genes, including two positively correlated F3'H (flavonoid-3'-hydroxylase) genes, two positively correlated ANS (anthocyanin synthase) genes, and three negatively correlated PPO (polyphenol oxidase) genes. Overexpression of CsMYB90 in tobacco resulted in dark-purple transgenic calluses. These results showed that the increased accumulation of three anthocyanins in ZK may promote purple-leaf coloration because of changes in the expression levels of genes, including CsMYB90, F3'Hs, ANSs, and PPOs. These findings reveal new insight into the molecular mechanism of anthocyanin biosynthesis in purple-leaf tea plants and provide a series of candidate genes for the breeding of anthocyanin-rich cultivars.

Regulation of the PTEN/PI3K/AKT pathway in RCC using the active compounds of natural products in vitro.

Since Professor Tu Youyou won the 2015 Nobel Prize in Physiology and Medicine for the discovery of artemisinin, which is used to treat malaria, increased attention has been paid to the extracts obtained from plants, in order to analyze their biological activities, particularly with regard to their antitumor activity. Therefore, the present study explored the biochemical properties of seven natural plant extracts on renal cell carcinoma (RCC). 786­O and OS­RC­2 cells were cultured and treated with different concentrations of the extracts. Then, cell viability, the IC50 value and proliferation was determined using a Cell Counting Kit­8 assay. Apoptosis and cell cycle distribution were evaluated via flow cytometry. The expression levels of proteins were assessed using western blotting, and cellular morphology was observed using a light microscope. The results showed that sophoricoside, aucubin, notoginsenoside R1 and ginsenoside Rg1 did not exhibit a cytotoxic effect on RCC cells, whereas ginsenoside Re and allicin exhibited a very slight inhibitory effect. Naringenin possessed the highest activity of the analyzed extracts. The IC50 values of naringenin on 786­O and OS­RC­2 cells were 8.91±0.33 and 7.78±2.65 µM, respectively. In addition, naringenin notably inhibited the proliferation of RCC cells by decreasing Ki67 expression, blocked cell cycle progression in the G2 phase by regulating expression of cell cycle proteins, and increased apoptosis by upregulating caspase­8 expression, downregulating Bcl­2 expression and altering the cellular morphology. Furthermore, naringenin inhibited cell proliferation and promoted apoptosis by upregulating the expression of PTEN at the protein level, downregulated the expression of PI3K and phosphorylated­(p­)AKT, but did not affect the expression of AKT, mTOR or p­mTOR. The seven plant extracts analyzed showed differing degrees of anti­RCC activity. Sophoricoside, aucubin, notoginsenoside R1 and ginsenoside Rg1 did not exhibit notable anti­RCC activity, whereas the effect of ginsenoside Re and allicin on RCC was considerably weak. However, naringenin showed potent anti­proliferative, apoptosis inducing and cell cycle arresting activity on RCC cells via regulation of the PTEN/PI3K/AKT signaling pathway.