Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymal-like cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal (E/M) tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.
Incorporating both diagnostic and therapeutic functions into a single nanoscale system is an effective modern drug delivery strategy. Combining liposomes with semiconductor quantum dots (QDs) has great potential to achieve such dual functions, referred to in this review as a liposomal QD hybrid system (L-QD). Here we review the recent literature dealing with the design and application of L-QD for advances in bio-imaging and drug delivery. After a summary of L-QD synthesis processes and evaluation of their properties, we will focus on their multifunctional applications, ranging from in vitro cell imaging to theranostic drug delivery approaches.
Barth syndrome (BTHS) is a mitochondrial disorder characterized by cardiomyopathy and skeletal muscle weakness. Disease results from mutations in the tafazzin (TAZ) gene, encoding a phospholipid transacylase. Defective tafazzin activity results in an aberrant cardiolipin (CL) profile. The feasibility of restoring the intracellular CL profile was tested by in vivo administration of exogenous CL in nanodisk (ND) delivery particles. Ninety mg/kg CL (as ND) was administered to doxycycline-inducible taz shRNA knockdown (KD) mice once a week. After 10 weeks of CL-ND treatment, the mice were sacrificed and tissues harvested. Liquid chromatography-mass spectrometry of extracted lipids revealed that CL-ND administration failed to alter the CL profile of taz KD or WT mice. Thus, although CL-ND were previously shown to be an effective means of delivering CL to cultured cells, this effect does not extend to an in vivo setting. We conclude that CL-ND administration is not a suitable therapy option for BTHS.
Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Lymphotoxin β receptor (LTβR) signaling plays an important role in autoimmune inflammations. LTβR-Ig fusion protein, LTβR blocking agent, has been used to treat SLE, while its mechanism remains to be fully elucidated. In this study, to investigate the expression of LTβR in the T cells of SLE patients and its roles in the pathogenesis of SLE, we isolated the peripheral blood T cells of SLE patients and normal controls to detect expression of LTβR by flow cytometry and RNA assay. T cells were also stimulated with LIGHT, a ligand of LTβR, and then detected for their LTβR expressions and apoptosis by flow cytometry. Also, their expressions of inflammatory factors and receptors were determined by RNA assay. The results showed that LTβR positive cells were 22.75%±6.98% in CD3+ cells of SLE patients, while there were almost no LTβR positive cells in CD3+ cells of normal persons. Moreover, LTβR expression was remarkably higher in CD3, CD4 and CD8 positive T cells of active SLE patients than non/low active patients (all P<0.05), and positively correlated with increased Ig level, decreased complement level and renal damage. Moreover, the stimulation of SLE T cells with LIGHT promoted higher expression of LTβR, IL-23R and IL-17A, and apoptosis of T cells. In conclusion, we demonstrated a high expression of LTβR in the T cells of SLE patients which may be associated with pathogenesis of SLE.
This study was aimed to introduce a novel entry point for pedicle screw fixation in the thoracic spine and compare it with the traditional entry point. A novel entry point was found with the aim of improving accuracy, safety and stability of pedicle screw technique based on anatomical structures of the spine. A total of 76 pieces of normal thoracic CT images at the transverse plane and the thoracic pedicle anatomy of 6 cadaveric specimens were recruited. Transverse pedicle angle (TPA), screw length, screw placement accuracy rate and axial pullout strength of the two different entry point groups were compared. There were significant differences in the TPA, screw length, and the screw placement accuracy rate between the two groups (P<0.05). The maximum axial pullout strength of the novel entry point group was slightly larger than that of the traditional group. However, the difference was not significant (P>0.05). The novel entry point significantly improved the accuracy, stability and safety of pedicle screw placement. With reference to the advantages above, the new entry point can be used for spinal internal fixations in the thoracic spine.
In this study, our objective was to evaluate effects of leptin on fracture healing in rats. Seventy two male Sprague-Dawley (SD) rats were randomized into 3 groups. Standardized femoral fractures were created in all the rats. Group A was treated with 1 mL normal saline (NS), group B with 0.3 μg/kg leptin in 1 mL NS, and group C with 0.5 μg/kg leptin in 1 mL NS for 2 weeks intraperitoneally. Each group was divided into three subgroups including 8 rats for evaluation at 2, 4 and 8 weeks. Radiological evaluation showed that callus formation of group B and C was all significantly higher than group A at 8 weeks (P=0.04 and P=0.013, respectively). There was no statistically significant difference in fracture healing between group B and group C at 8 weeks (P=0.197). Histological evaluation revealed fracture healing of group B and C was better than group A at 4 weeks (P=0.01 and P=0.002, respectively) and 8 weeks (P=0.008 and P=0.003, respectively). Micro-computed tomography (Micro-CT) analysis demonstrated that greater amounts of bony callus and evidence of bone fusion were observed in group B and C at 4 weeks (P=0.02 and P=0.04, respectively) and 8 weeks (P=0.005 and P=0.001, respectively) compared to group A. Group C also had better fracture healing than group B at 8 weeks (P=0.01). In conclusion, leptin has a positive effect on rat femoral fracture healing.
Microglia activation and white matter injury coexist after repeated episodes of mild brain trauma and ischemic stroke. Axon degeneration and demyelination can activate microglia; however, it is unclear whether early microglia activation can impair the function of white matter tracts and lead to injury. Rat corpus callosum (CC) slices were treated with lipopolysaccharide (LPS) or LPS + Rhodobacter sphaeroides (RS)-LPS that is a toll-like receptor 4 (TLR-4) antagonist. Functional changes reflected by the change of axon compound action potentials (CAPs) and the accumulation of β-amyloid precursor protein (β-APP) in CC nerve fibers. Microglia activation was monitored by ionized calcium binding adaptor-1 immunofluorescent stain, based on well-established morphological criteria and paralleled proportional area measurement. Input-output (I/O) curves of CAPs in response to increased stimuli were significantly downshifted in a dose-dependent manner in LPS (0.2, 0.5 and 1.0 µg/mL)-treated slices, implying that axons neurophysiological function was undermined. LPS caused significant β-APP accumulation in CC tissues, reflecting the deterioration of fast axon transport. LPS-induced I/O curve downshift and β-APP accumulation were significantly reversed by the pre-treatment or co-incubation with RS-LPS. RS-LPS alone did not change the I/O curve. The degree of malfunction was correlated with microglia activation, as was shown by the measurements of proportional areas. Function of CC nerve fibers was evidently impaired by microglia activation and reversed by a TLP-4 antagonist, suggesting that the TLP-4 pathway lead to microglia activation.
Parkinson’s disease (PD) associated leucine-rich repeat kinase 2 (LRRK2) mutants have shown pathogenic effects on variety of subcellular processes.Two small GTPases Rac1 and Rab29 have been indicated as possible downstream effectors participating in LRRK2 signaling but their detail mechanisms remain unclear. In this study, we have used biochemical and cell biology approaches to address whether two GTPases interact with LRRK2 and hence function differently in LRRK2 mediated pathogenesis.Here we show thatRac1 and Rab29 specifically interact with LRRK2with higher affinity for Rab29and with different preference in functional domain binding. Mutant Rab29 but not Rac1 alters theendosome-to-TGN retrograde trafficking of a cargo protein cation-independent mannose-6-phosphate receptor (CI-M6PR) and its stability. On the other hand, overexpressedwild type Rab29 but not Rac1 rescue the altered retrograde membrane trafficking induced by the pathogenic mutant LRRK2G2019S. Furthermore, both Rac1 and Rab29 can rescue the neurite shortening in differentiated SH-SY5Y cells induced by LRRK2G2019S. Our study strongly suggests that Rac1 and Rab29 are involved in the distinct functions as downstream effectors in LRRK2 signaling pathways.
Infections due to Fusarium species are collectively referred to as fusariosis. Fusarium oxysporum has been reported to cause keratitis, onychomycosis, skin infections, catheter associated fungemia and has not been described as a cause of urinary tract infection. Here, we present the first case of fusariosis with urinary tract involvement in a 67 year old male, with chronic kidney disease and type 2 diabetes mellitus. This case illustrates the ever increasing spectrum of rare but offending pathogenic fungi. Early diagnosis of infection with a specific pathogen may lead to changes in antifungal therapy and may be critical for an improved outcome.