Medium-sized peptides from microbial sources with potential for antibacterial drug development.

Covering: 1993 to the end of 2022As the rapid development of antibiotic resistance shrinks the number of clinically available antibiotics, there is an urgent need for novel options to fill the existing antibiotic pipeline. In recent years, antimicrobial peptides have attracted increased interest due to their impressive broad-spectrum antimicrobial activity and low probability of antibiotic resistance. However, macromolecular antimicrobial peptides of plant and animal origin face obstacles in antibiotic development because of their extremely short elimination half-life and poor chemical stability. Herein, we focus on medium-sized antibacterial peptides (MAPs) of microbial origin with molecular weights below 2000 Da. The low molecular weight is not sufficient to form complex protein conformations and is also associated to a better chemical stability and easier modifications. Microbially-produced peptides are often composed of a variety of non-protein amino acids and terminal modifications, which contribute to improving the elimination half-life of compounds. Therefore, MAPs have great potential for drug discovery and are likely to become key players in the development of next-generation antibiotics. In this review, we provide a detailed exploration of the modes of action demonstrated by 45 MAPs and offer a concise summary of the structure-activity relationships observed in these MAPs.

Research Progress on the Combination of Quorum-Sensing Inhibitors and Antibiotics against Bacterial Resistance.

Bacterial virulence factors and biofilm development can be controlled by the quorum-sensing (QS) system, which is also intimately linked to antibiotic resistance in bacteria. In previous studies, many researchers found that quorum-sensing inhibitors (QSIs) can affect the development of bacterial biofilms and prevent the synthesis of many virulence factors. However, QSIs alone have a limited ability to suppress bacteria. Fortunately, when QSIs are combined with antibiotics, they have a better therapeutic effect, and it has even been demonstrated that the two together have a synergistic antibacterial effect, which not only ensures bactericidal efficiency but also avoids the resistance caused by excessive use of antibiotics. In addition, some progress has been made through in vivo studies on the combination of QSIs and antibiotics. This article mainly expounds on the specific effect of QSIs combined with antibiotics on bacteria and the combined antibacterial mechanism of some QSIs and antibiotics. These studies will provide new strategies and means for the clinical treatment of bacterial infections in the future.

Biosynthesis and Gene Regulation of Rhamnolipid Congeners.

Rhamnolipid congeners have been widely used in agriculture and biomedicine as potent surfactants. They have recently attracted attention due to their diverse and versatile biological functions, which include an important bacterial virulence factor that makes them attractive targets for research into biosynthetic pathways and gene regulation. The intricate gene expression and regulation network controlling their biosynthesis remain to be completely understood. This article summarizes current knowledge about the biosynthesis pathways and regulatory mechanisms of rhamnolipid congeners, that meet the pharmacological needs of human health and agriculture.

Psychological suzhi and academic achievement in Chinese adolescents: A 2-year longitudinal study.

BACKGROUND: In the Chinese educational system, there has been an ongoing debate between using examination- or quality-oriented education. The Chinese concept of psychological suzhi was proposed based on quality-oriented education, and a positive link between psychological suzhi and academic achievement was found by cross-sectional studies; however, studies examining their longitudinal relationship are still lacking. AIMS: To examine the longitudinal trajectories of Chinese adolescents' academic achievement and the longitudinal effects of psychological suzhi on academic achievement trajectories. SAMPLE: Participants were 3,587 adolescents (Mage  = 14.85 years, 51.1% male) in grades 7 and 10, from 10 secondary schools in southwest China. METHOD: A 2-year (four-wave) longitudinal study was conducted, and growth mixture models were used to analyse the data. RESULTS AND CONCLUSIONS: Four distinct developmental trajectories of academic achievement were identified (i.e., high-positive growth, middle-negative growth, low-stable, and lowest-stable) that were significantly predicted by different levels of psychological suzhi, particularly the dimension of cognitive quality. Cognitive quality was strongly associated with the initial academic achievement values in the high-positive growth group and linked to achievement rate (decreasing) in the middle-negative growth group. However, individuality quality and adaptability quality had a buffering effect on the rate of achievement decreasing in the middle-negative growth group. This study not only highlighted the promotive role of high cognitive quality on high levels of achievement (static) but also indicated the protective role of non-cognitive factors (i.e., individuality and adaptability) against a decreasing rate of academic achievement (dynamic).

Metformin enhances the sensitivity of colorectal cancer cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway.

Metformin and cisplatin have been widely studied as antitumor agents. However, the effect of metformin combined with cisplatin has not been investigated in colorectal cancer (CRC) cells. This study was aimed to explore the effect of metformin or/and cisplatin on cell viability, apoptosis, and the related signaling pathways in CRC SW480 and SW620 cells. We found that metformin or cisplatin inhibited cell viability of SW480 and SW620 cells in a concentration- and time-dependent manner. Furthermore, metformin combined with cisplatin obviously inhibited cell viability, decreased colony formation, induced apoptosis, mediated cleavage of caspase-9, caspase-3 and PARP, activated mitochondrial membrane potential, downregulated Mcl-1 and Bcl-2 expression, upregulated Bak and Bax expression, and increased reactive oxygen species (ROS) production, compared to the individual agent in SW480 and SW620 cells, which were attenuated by N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, NAC could recover the downregulation of p-PI3K and p-Akt treated with combination of metformin and cisplatin, which subsequently activated the PI3K/Akt signaling pathway. Taken together, our results demonstrated that metformin enhanced the sensitivity of CRC cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway.

[Down-regulation of miR-205-5p enhances pro-apoptotic effect of 3-bromopyruvate on human nasopharyngeal carcinoma CNE2Z cells].

OBJECTIVE: To investigate the effect of down-regulation of miR-205-5p on 3-bromopyruvate-induced apoptosis in human nasopharyngeal carcinoma CNE2Z cells. METHODS: Nasopharyngeal carcinoma CNE2Z cells were transfected with miR- 205-5p-mimic or miR-205-5p-inhibitor, treated with 80 µmol/L 3-bromopyruvate alone, or exposed to both of the treatments. The proliferation of the treated cells was examined with MTT assay, and early apoptosis of the cells was detected using a mitochondrial membrane potential detection kit (JC-1). DAPI fluorescence staining was used to detect morphological changes of the cell nuclei and late cell apoptosis; Annexin V-FITC/PI double staining was employed to detect the cell apoptosis rate. Western blotting was used to detect the expressions of Bcl-2, Bax, Mcl-1 and Bak proteins. RESULTS: Exposure to 3-bromopyruvate significantly inhibited the proliferation of CNE2Z cells, and increasing the drug concentration and extending the treatment time produced stronger inhibitory effects. Treatment with 80 µmol/L 3-bromopyruvate for 24, 48 and 72 h resulted in inhibition rates of (45.7±1.21)%, (64.4±2.02)% and (78.3±1.55)% in non-transfected CNE2Z cells, respectively; the inhibition rates were (27.7±1.04)%, (34.8±2.10)% and (44.3±1.57)% in the cells transfected with miR-205-5p-mimic, and were (80.5 ± 0.94)%, (87.9 ± 0.50)% and (93.8 ± 1.16)% in cells transfected with miR-205-5p-inhibitor, respectively. The results of mitochondrial membrane potential detection showed that the relative proportion of red and green fluorescence decreased significantly in miR-205-5p-inhibitor-transfected cells with 3-bromopyruvate treatment. Combined treatment of the cells with 3-bromopyruvate and miR-205-5p-inhibitor transfection obviously increased nuclear fragmentation and nuclear pyknosis and significantly increased cell apoptotic rate as compared with the two treatments alone (P < 0.01), causing also decreased expressions of Bcl-2 and Mcl-1 proteins and increased expressions of Bax and Bak proteins. CONCLUSIONS: Inhibition of miR-205-5p enhances the proapototic effect of 3-bromopyruvate in CNE2Z cells possibly in relation to the down-regulation of Mcl-1 and Bcl-2 and the up-regulation of Bak and Bax proteins.

miR-205-5p regulates epithelial-mesenchymal transition by targeting PTEN via PI3K/AKT signaling pathway in cisplatin-resistant nasopharyngeal carcinoma cells.

Epithelial-mesenchymal transition (EMT) symbolizes the predominant program of advanced-stage cancer, it is critical in cancer progression, metastasis, and chemotherapy resistance. In this study, the metastatic properties of nasopharyngeal carcinoma (NPC) cells were evaluated by morphological examination, wound healing assay, migration and invasion assay. Western blotting and qRT-PCR were used to ascertain the expression of markers which were associated with EMT. The effects of miR-205-5p on invasion, migration, EMT and proliferation of NPC cells were evaluated and the molecular mechanisms of their interaction were explored. In this study, we manifested firstly that the expression of miR-205-5p in cisplatin-resistant NPC cell line HNE1/DDP was obviously up-regulated than that in its parental cell line HNE1. Then we analyzed the specific role of miR-205-5p through functional assays by transfecting specific mimics and inhibitors. The results indicated that low expression of miR-205-5p restrained EMT progression of HNE1/DDP cells. Further studies on the mechanism of miR-205-5p manifested that PTEN was a downstream candidate gene of miR-205-5p, down-regulated PTEN expression could counteract the effect of miR-205-5p inhibitors, and the regulation of EMT by miR-205-5p on HNE1/DDP cells depended on the PI3K/AKT signaling pathway. Overall, our results indicated that miR-205-5p was targeting PTEN to regulate EMT through the PI3K/AKT pathway. This study will supply a new treatment target for advanced NPC.

Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways.

The age-related functional exhaustion limits potential efficacy of mesenchymal stem cells (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb-B2 receptor tyrosine kinase 4 ( ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged-MSC), ERBB4-engineered aged MSC (ER4-aged-MSC) conferred resistance to oxidative stress-induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4-aged-MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged-MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT), and phosphorylated ERK expression under hypoxia. ER4-aged-MSC secreted higher levels of angiopoietin, epithelial neutrophil activating peptide 78, VEGF, and fibroblast growth factor 2, and enhanced tube formation in HUVEC. The impact of ERBB4 on protein expression, proangiogenesis, cell behavior, and cytokine secretion was abolished by inhibiting PI3K/AKT and MAPK/ERK signaling pathway.-Liang, X., Ding, Y., Lin, F., Zhang, Y., Zhou, X., Meng, Q., Lu, X., Jiang, G., Zhu, H., Chen, Y., Lian, Q., Fan, H., Liu, Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways.

The Effect of Psychological Suzhi on Problem Behaviors in Chinese Adolescents: The Mediating Role of Subjective Social Status and Self-esteem.

In this study, we examined subjective social status (SSS) and self-esteem as potential mediators between the association of psychological suzhi and problem behaviors in a sample of 1271 Chinese adolescents (44.5% male, grades 7-12). The results showed that SSS and self-esteem were fully mediating the relationship between psychological suzhi and problem behaviors. Moreover, the indirect effect was stronger via self-esteem than via SSS. These findings perhaps provide insight into the preliminary effect that SSS and self-esteem underlie psychological suzhi's effect on adolescents' problem behaviors, and also are important in helping school-teachers and administrators to develop a better understanding of problem behaviors in their schools as a pre-requisite to the development of more effective behaviors management practices from the perspective of psychological suzhi. Implications and limitations in the present study have also been discussed.