Latest ArticlesWith the worldwide spread of multi-drug resistant (MDR) bacteria, bacterial resistance has become a major issue affecting human health. Although traditional methods for obtaining antibiotics by screening bacterial strains have found the most available antibiotics for us, this method has resulted in fewer and fewer antibiotics in the past few decades and is increasingly difficult to find the new structure of the compound entity. At present, there are few drugs that can fight super-resistant bacteria in the clinic or even research. therefore, the development and application of new technologies to address the issue of bacterial resistance is imminent. Since the first bacterial genome was sequenced more than 20 years ago, a large number of bacterial genomic sequence information can provide clues for the discovery of new antibiotics. In this review, we briefly outline the available data sources and highlight the use of genomic mining and metagenomics in discovery of new antibiotics.
Due to the potent bactericidal activity and low incidence of drug resistance, the novel cyclic lipopeptide antibiotic - daptomycin has emerged as one of the first line antimicrobial agents in the treatment of serious infections caused by gram-positive resistant pathogens. This review summarizes the research advances of daptomycin in recent years, mainly including spectrum of antimicrobial activity, biosynthesis, mode of action, mechanism of drug resistance, structure-activity relationships, surotomycin and siderophore-daptomycin conjugate to kill multidrug resistant Acinetobacter baumannii. The findings summarized in this review highlight the directions of next-generation of daptomycin derivatives.
9-Acetoxycycloberberine (1) with a unique skeleton was first identified to display a potent antimicrobial profile against methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 1-16 μg·mL-1. Taking the compound as a lead, 14 target cycloberberine analogues with diverse structures, such as berberine and chelerythrine derivatives, were synthesized and evaluated for their anti-bacterial activities. Analysis of the structure-activity relationship revealed that:① ring E was essential for the activity; ② the removing of ring B decreased the activity against MRSA. However, the antimicrobial activity against vancomycin-resistant Enterococcus faecium (VRE) was improved; ③ the introduction of a suitable rigid substituent at the 9-position was beneficial for the activity. Among them, compound 9a showed the most potential activity against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA isolates with MIC values of 0.5-1 μg·mL-1, suggesting a different mechanism from clinical drugs. It displayed higher stability in blood. Therefore, we consider 9a worthy of further investigation. The results provide key scientific evidence for development of such compounds into a new type of anti-MRSA candidates.
Sansanmycins (SSs), produced by Streptomyces sp. SS, belong to uridyl peptide antibiotics which exhibit a good inhibitory effect on Mycobacterium tuberculosis and Pseudomonas aeruginosa. They share a unique chemical scaffold with a 4', 5'-enamide-3'-deoxyuridine attached to DABA (N-methyl-2, 3-diaminobutyryl) which was located in the peptide chain through peptide bond. In order to study the function of related genes and to employ synthetic biology to gain new SS derivatives, we obtained a complete SS biosynthetic gene cluster and heterologously expressed it in Streptomyces coelicolor M1146, M1152 and M1154. Fermentation broth of the recombinant strains were detected using HPLC and HPLC-MS/MS, and the result showed that SS-A was successfully produced in the three strains, and its production level in S. coelicolor M1154 was similar to the original wild type strain. In addition, a potential SS analogue named as SS-1154 was discovered from the fermentation broth of S. coelicolor M1154.
Transient receptor potential vanilloid member 3 (TRPV3) is a temperature-sensitive cation channel protein, which contributes to nociception, itch, hair growth, emotional control and the pathophysiology of migraine. However, research progress on TRPV3 fundamental molecular biology is rather slow, compared to other TRP channels due to the lack of its selective antagonists. It's necessary to identify TRPV3 selective antagonists for the study on TRPV3 physiological functions. In this study, several selective TRPV3 antagonists were identified by ligand-based virtual screening of shape-based similarity and electrostatic matching. The most potent one (V-39) blocked 2-APB-activated currents in a stable human TRPV3 expressed HEK293T cell line with IC50=18.0 ±1.1 μmol·L-1 (n=4). Besides, the interaction pattern between TRPV3 and its antagonists were studied through docking the antagonists into a homology model (TRPV3_HM4) generated from the crystal structure of TPRV1. The docking results show that the binding site of TRPV3 locates between linker domain (of N-terminus and TM1) and TRP Box. There are a π-π stacking interaction and hydrogen bonding interactions between compound V-39 and residues His-310, His-314 and Arg-577 of the pocket. Identification of these antagonists provides new probes for understanding the pharmacological function of TRPV3 channel.
To compare static and dynamic metabolomics data analysis of CUMS (chronic unpredictable mild stress)-induced depression, GC-MS spectrometry was conducted on the plasma metabolome. S-Plot and ANOVA (analysis of variance)-simultaneous component analysis (ASCA) were respectively applied to static and dynamic analysis of metabolomics data. Static metabolomics data analysis revealed three typical plasma metabolites including propionic acid, D-allose, and 9, 12, 15-octadecatrienoic acid, while dynamic me-tabolomics data analysis found seven typical metabolites including propionic acid, D-allose, My-inositol, me-thylamine, etc. The abundances of typical metabolites observed by dynamic metabolomics data analysis were consistent with the variation trends of body weight and sugar water preference rate of CUMS rats. In conclusion, dynamic metabolomics analysis revealed more typical plasma metabolites, which have the potential to explain variations of body weight and behavior parameter of CUMS-induced depression rats. Combination of static and dynamic metabolomics data analysis may provide a strong support to the pathological study of complex diseases.
This study was designed to investigate the role of CD36 in palmitic acid (PA)-induced apoptosis of astrocytes and the potential mechanisms of the action. MTT assay was used to detect cell viability and TUNEL assay to detect cell apoptosis. It was found that PA significantly decreased astrocyte cell viability and increased cell apoptosis. The uptake of BODIPY FL C16 by astrocytes was measured by flow cytometry. The results showed that CD36 played a key role in the process of PA uptake by astrocytes. The changes of intracellular calcium concentration were detected by FLIPR real-time fluorescence recording system. It was found that IP3R mediated PA signal to induce intracellular calcium release and finally caused endoplasmic reticulum calcium depletion. The intracellular ROS level was detected with CM-H2DCFDA fluorescence staining. The ROS level was induced by PA in astrocytes. The effect was blocked by CD36 inhibitor SSO through inhibition of the uptake of PA. PA-induced calcium overload and ROS increase were prevented by IP3R inhibitor APB. SSO, APB and antioxidant NAC all had significant inhibitory effects on PA-induced astrocyte cell viability decrease. In conclusion, CD36 mediates the translocation of PA into astrocytes, which leads to calcium overload, oxidative stress and eventually cell apoptosis.
The chemical constituents of the fruits of Chaenomeles sinensis (Thouin) Koehne were investigated using chromatographic methods, including Diaion HP-20, Toyopearl HW-40, MCI Gel CHP-20, ODS, Silica gel chromatography and semi-preparative-HPLC. Three compounds were isolated and their structures were elucidated with spectral data and physicochemical properties, which were identified as chaenomeles alkaloid A (1), ginsenine (2) and 1, 2, 3, 4-tetrahydro-1-methyl-β-carboline-3-car-boxylic acid (3). Among those, compound 1 is a new alkaloid, compound 2 and 3 were isolated from this plant for the first time. To investigate the protective effect of compounds 1-3 on Rat adrenal pheochromocytoma (PC-12) injury induced by the β-amyloid protein (Aβ25-35). The results show that compounds 2 and 3 have a significant protective effect on the PC12 cells exposed to Aβ25-35.
Ginsenoside Rg1 is a common component of a variety of stroke and diabetes medications, but its anti-stroke effect in diabetic patients is unclear. The aim of this research is to test the therapeutic effect of Rg1 on ischemic stroke in diabetic rats, and elucidate the effect of Rg1 on post-stroke neuro-inflammation. Rg1 significantly reduced the infarct area percent, increased the behavioral score, and reduced the brain water content in diabetic rats after stroke in the diabetic rats. Rg1 reduced the post-stroke inflammatory response and decreased the expression of high mobility group box1 (HMGB1) protein significantly. Elevated level of HMGB1 activity by supplementing exogenous HMGB1 protein abolished the anti-stroke effect of Rg1, which suggests that HMGB1 is involved into the anti-stroke effect of Rg1 in the diabetic rats.
Poly(ADP-ribose) polymerase (PARP)-1 and PARP2 function as ADP-ribosylases involved in DNA repair. PARP1/2 is highly expressed in cancers and emerged as an attractive target for antitumor drug. In this study, we investigated the antitumor activity of a novel PARP1/2 inhibitor YHP-743 in vitro and in vivo. The results showed that YHP-743 had potent enzymatic inhibitory activity against PARP1 and PARP2 to down-regulate the PAR level. YHP-743 not only inhibited breast cancer cells with genes deficiency of homologous recombination repair, but also potentiated chemotherapy agent's cytotoxicity, such as temozolomide, topotecan, cisplatin and doxorubicin. YHP-743 elicited good antitumor activity in combination with temo-zolomide in vivo.
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