Biosynthesis and Chemical Synthesis of Albomycin Nucleoside Antibiotics.

The widespread emergence of antibiotic-resistant bacteria highlights the urgent need for new antimicrobial agents. Albomycins are a group of naturally occurring sideromycins with a thionucleoside antibiotic conjugated to a ferrichrome-type siderophore. The siderophore moiety serves as a vehicle to deliver albomycins into bacterial cells via a "Trojan horse" strategy. Albomycins function as specific inhibitors of seryl-tRNA synthetases and exhibit potent antimicrobial activities against both Gram-negative and Gram-positive bacteria, including many clinical pathogens. These distinctive features make albomycins promising drug candidates for the treatment of various bacterial infections, especially those caused by multidrug-resistant pathogens. We herein summarize findings on the discovery and structure elucidation, mechanism of action, biosynthesis and immunity, and chemical synthesis of albomcyins, with special focus on recent advances in the biosynthesis and chemical synthesis over the past decade (2012-2022). A thorough understanding of the biosynthetic pathway provides the basis for pathway engineering and combinatorial biosynthesis to create new albomycin analogues. Chemical synthesis of natural congeners and their synthetic analogues will be useful for systematic structure-activity relationship (SAR) studies, and thereby assist the design of novel albomycin-derived antimicrobial agents.

Vascular Endothelial Growth Factor-Transfected Bone Marrow Mesenchymal Stem Cells Improve the Recovery of Motor and Sensory Functions of Rats With Spinal Cord Injury.

STUDY DESIGN: Basic science. OBJECTIVE: The aim of this study was to examine the effect of vascular endothelial growth factor (VEGF)-transfected bone marrow mesenchymal stem cells (BMSCs) on the recovery of motor and sensory functions of rats with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: There is no effective treatment to protect against SCI. BMSCs have been widely applied to the treatment of nervous system damage due to the function of prompt neurite growth and inhibition of demyelination following injury. METHODS: VEGF-transfected BMSCs were injected to rats with SCI and the recovery of motor and sensory functions was observed. The Basso, Beattie, and Bresnahan, mechanical withdrawal threshold and thermal withdraw latency grading was conducted to assess the recovery status of motor and sensory functions of the SCI rats. The expression of VEGF, CD31, and NF200 was detected by immunofluorescence. RESULTS: The recovery of the rat motor and sensory functions in the VEGF-transfected BMSC (BMSC-VEGF) group was higher than those of the other groups with the exception of the Sham group (P < 0.05). The expression of the CD31 and NF200 proteins in the rat SCI regions was the highest in the BMSC-VEGF group, whereas the survival of BMSC in the BMSC-VEGF group was increased compared with that in the BMSC-Ad group. In addition, the injection of VEGF-transfected BMSCs can improve the angiogenesis of the injured area and retain the survival of injected cells and neurons. CONCLUSION: The injection of BMSC-VEGF improved the recovery of motor function in SCI rats. LEVEL OF EVIDENCE: N/A.

Glycyrrhizin suppresses inflammation and cell apoptosis by inhibition of HMGB1 via p38/p-JUK signaling pathway in attenuating intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is associated with the nucleus pulposus (NP) cells inflammation and apoptosis. Previous studies have shown that glycyrrhizin (GL) is a valid inhibitor of the high-mobility group box-1 gene (HMGB1) which expressed much higher in an inflammatory condition. However, it is not known whether GL protects against IDD by the inhibition of HMGB1. To study the effect and mechanism of glycyrrhizin on intervertebral disc degeneration. We analyzed the expression of HMGB1 in different degree of degenerate disc tissues. Interleukin 1 beta (IL-1ß) was used in stimulating the NP cells to degeneration. We used recombined human HMGB1 to resist the function of GL to explore whether GL acted via the target of HMGB1. Our study showed that the expression of HMGB1 markedly increased in severely degenerated disc tissues. IL-1ß promoted the progress of IDD, and the stimulation of GL could reverse the effects of IL-1ß. Moreover, p38 and p-JNK were significantly suppressed by GL stimuli. These results suggested that GL prevented NP degradation via restraining inflammation and cell apoptosis by inhibition of HMGB1 via p38/p-JNK signaling pathway. GL may become a novel cytokine for the therapy of IDD in the future.

Transplantation of VEGF-mediated bone marrow mesenchymal stem cells promotes functional improvement in a rat acute cerebral infarction model.

Vascular endothelial growth factor (VEGF) stimulation and bone marrow mesenchymal stem cell (BMSC) transplantation have been implicated in the treatment of acute cerebral infarction for their pivotal roles in behavioral recovery, neuroprotection, neurogenesis, and angiogenesis. However, the effects of BMSC transplants are likely limited because of low transplant survival after acute cerebral infarction, and delivery of VEGF alone also has limited effects on recovery because the protein is cleared quickly. This study attempted to explore whether VEGF could be transferred into BMSC via an adenovirus and whether transplanting VEGF-transfected BMSC into the rat brain provides sufficient neuroprotection after transient middle cerebral artery occlusion. The adenovirus carried VEGF into BMSC (Ad-VEGF-BMSC), and purified adenovirus was transferred into BMSC (Ad-BMSC). Western blots were used to detect the expression of VEGF protein after transfection. Rats exposed to 90-min middle cerebral artery occlusion (MCAO) were treated with Ad-VEGF-BMSC, Ad-BMSC, BMSC and Dulbecco's Modified Eagle's Medium (DMEM) after ischemia reperfusion for 24h. The Sham group only received surgery. After transplantation of Ad-VEGF-BMSC into the perifocal area of the ischemic rat brain, we found increased expression and secretion of VEGF and BDNF as well as a higher level of MAP2, increased microvascular density, improved behavioral function and enhanced BMSC survival. Our results indicated that transplantation of Ad-VEGF-BMSC improved ischemic neurological deficiency after MCAO in rats. This finding provides a potential valuable therapeutic intervention for cerebral ischemic diseases.

Functional research and molecular mechanism of Kainic acid-induced denitrosylation of thioredoxin-1 in rat hippocampus.

Thioredoxin-1 (Trx1) has long been recognized as a redox regulator, and is implicated in the inhibition of cell apoptosis. Trx1 is essential for the maintenance of the S-nitrosylation of molecules in cells. The S-nitrosylation of Trx1 is essential for the physiological function such as preservation of the redox regulatory activity. The mechanisms underlying Trx1 denitrosylation induced by kainate acid (KA) injection still remain uncharacterized. Our results showed that the S-nitrosylation levels of Trx1 were decreased subsequent to KA injection and that the glutamate receptor 6 (GluR6) antagonist NS102 could inhibit the denitrosylation of Trx1. Moreover, the denitrosylation of Trx1 following KA treatment could be suppressed by the Fas ligand (FasL) antisense oligodeoxynucleotides (AS-ODNs), the Trx reductase (TrxR) inhibitor dinitrochlorobenzene (DNCB), or the Nitric oxide (NO) donors sodium nitroprusside (SNP) and S-nitrosoglutathione (GSNO). Subsequently, these mechanisms were morphologically validated by cresyl violet staining, in situ TUNEL staining to detect the survival of CA1 and CA3/DG pyramidal neurons. NS102, FasL AS-ODNs, GSNO and SNP could provide neuroprotection of the pyramidal neurons of CA1 and CA3/dentate gyrus (DG) regions by attenuating Trx1 denitrosylation. Our results also showed that the denitrosylation of Trx1 induced by KA injection can active the caspase-3 which results in apoptosis.

Effects of epidermal growth factor and basic fibroblast growth factor on the proliferation and osteogenic and neural differentiation of adipose-derived stem cells.

Stem cells used for clinical tissue regeneration therapy should have the capacity of self-renewal, high proliferation, and differentiation and be able to be transplanted in large numbers. Although high concentrations of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) may induce the differentiation of stem cells, these factors have been widely used to enhance the propagation of stem cells, including adipose-derived mesenchymal stem cells (ASCs). However, the effects of low concentrations of EGF and bFGF on stem cells need to be evaluated carefully. This study illustrates that low concentrations of EGF (5 ng/mL) and bFGF (10 ng/mL) increase the proliferative ability of ASCs and induce the typical spindle-shaped cell morphology. EGF and bFGF added to medium promoted neural lineage differentiation and impaired the mesodermal differentiation ability of ASCs. This study demonstrates that even low concentrations of EGF and bFGF may limit the differentiation ability of stem cells during stem cell expansion in vitro. EGF and bFGF supplementation should be carefully considered in stem cells for clinical applications.

Preparation of gentamicin-loaded electrospun coating on titanium implants and a study of their properties in vitro.

PURPOSE: Implant-related infections are disastrous complications in the clinic, and there are no effective therapies. In this preliminary study, gentamicin-loaded coating on titanium implants was prepared using the electrospinning technique, and some properties of the coating titanium implants were studied. METHODS: We adopted the electrospinning technique to prepare gentamicin-coated titanium implants. The surface structure of the coating implants was observed using scanning electron microscope. An elution study was performed to determine the release behavior of the gentamicin from the coating. The antibacterial efficacy and quantitative analysis of the bacterial adhesion of Staphylococcus aureus were evaluated in vitro, and the cytotoxicity of the coated titanium implants on osteoblasts was investigated in vitro. RESULTS: The morphology of the gentamicin-coated titanium implants exhibited nanofibers, and the release of gentamicin showed an initial gentamicin burst followed by a slow release. The gentamicin-coated titanium implants had a persistent antibacterial efficacy for 1 week and significantly reduced the adhesion of the Staphylococcus aureus compared with bare titanium implants in vitro. There was no cytotoxicity observed in vitro for the gentamicin-coated implants. CONCLUSION: The gentamicin-coated titanium implants, which were prepared using an electrospinning technique, present many advantages and may be considered to prevent and treat the implant-related infections.