Macrophage activation and persistent inflammation contribute to the pathological process of spinal cord injury (SCI). It was reported that M2 macrophages were induced at 3–7 days after SCI but M2 ...markers were reduced or eliminated after 1 week. By contrast, M1 macrophage response is rapidly induced and then maintained at injured spinal cord. However, factors that modulate macrophage phenotype and function are poorly understood. We developed a model to distinguish bone‐marrow derived macrophages (BMDMs) from residential microglia and explored how BMDMs change their phenotype and functions in response to the lesion‐related factors in injured spinal cord. Infiltrating BMDMs expressing higher Mac‐2 and lower CX3CR1 migrate to the epicenter of injury, while microglia expressing lower Mac‐2 but higher CX3CR1 distribute to the edges of lesion. Myelin debris at the lesion site switches BMDMs from M2 phenotype towards M1‐like phenotype. Myelin debris activates ATP‐binding cassette transporter A1 (ABCA1) for cholesterol efflux in response to myelin debris loading in vitro. However, this homeostatic mechanism in injured site is overwhelmed, leading to the development of foamy macrophages and lipid plaque in the lesion site. The persistence of these cells indicates a pro‐inflammatory environment, associated with enhanced neurotoxicity and impaired wound healing. These foamy macrophages have poor capacity to phagocytose apoptotic neutrophils resulting in uningested neutrophils releasing their toxic contents and further tissue damage. In conclusion, these data demonstrate for the first time that myelin debris generated in injured spinal cord modulates macrophage activation. Lipid accumulation following macrophage phenotype switch contributes to SCI pathology. GLIA 2015;63:635–651
Main Points
Myelin debris generated in injured spinal cord switches macrophages from M2 phenotype towards M1‐like phenotype and results in the formation of foamy cells and lipid plaques.
Foamy macrophages are pro‐inflammatory because they are neurotoxic, defective apoptotic/necrotic cell clearance and showed delayed wound healing.
N6‐methyladenosine (m6A) has emerged as the most prevalent post‐transcriptional modification on mRNA that contributes prominently to tumorigenesis. However, the specific function of m6A ...methyltransferase methyltransferase‐like 3 (METTL3) in colorectal cancer (CRC) remains elusive. Herein, we explored the biological function of METTL3 in CRC progression. Clinically, METTL3 was frequently upregulated in CRC tissues, cell lines, and plasma samples and its high expression predicted poor prognosis of CRC patients. Functionally, knockdown of METTL3 significantly repressed CRC cell proliferation and migration in vitro, while its overexpression accelerated CRC tumor formation and metastasis both in vitro and in vivo. Mechanistically, METTL3 epigenetically repressed YPEL5 in an m6A‐YTHDF2‐dependent manner by targeting the m6A site in the coding sequence region of the YPEL5 transcript. Moreover, overexpression of YPEL5 significantly reduced CCNB1 and PCNA expression. Collectively, we identified the pivotal role of METTL3‐catalyzed m6A modification in CRC tumorigenesis, wherein it facilitates CRC tumor growth and metastasis through suppressing YPEL5 expression in an m6A‐YTHDF2‐dependent manner, suggesting a promising strategy for the diagnosis and therapy of CRC.
Here, we demonstrate that methyltransferase‐like 3 (METTL3)‐catalyzed N6‐methyladenosine (m6A) modification facilitates tumor growth and metastasis in colorectal cancer (CRC). METTL3 can reduce YPEL5 expression in an m6A‐YTHDF2‐dependent manner. Our findings highlight a novel m6A regulatory mechanism, with ‘writer’ METTL3, ‘reader’ YTHDF2, and ‘target’ YPEL5 being promising diagnostic or therapeutic targets in CRC.
Different-shaped ultrafine MoNbTaW high-entropy alloy powders were firstly prepared by a convenient mechanical alloying method. The phase composition and microstructure of the powders were ...characterized. The powders are ultrafine with nano-sized grains and a good homogeneous microstructure. All the powders have a single body-centered cubic solid solution phase and form the high-entropy alloy during mechanical alloying. These powders with different shapes are quite attractive for developing high-performance MoNbTaW high-entropy alloy bulk and coatings combined with a following sintering, spraying, or additive manufacturing technique.
Benzalkonium chloride (BAC) is the most common preservative in ophthalmic preparations. Here, we investigated the corneal alternations in rabbits following exposure to BAC. Twenty-four adult male New ...Zealand albino rabbits were randomly divided into three groups. BAC at 0.01%, 0.05%, or 0.1% was applied twice daily to one eye each of rabbits for 4 days. The contralateral untreated eyes were used as control. Aqueous tear production and fluorescein staining scores of BAC-treated eyes were compared with those of controls. The structure of the central cornea was examined by in vivo confocal microscopy. Expression of mucin-5 subtype AC (MUC5AC) in conjunctiva was detected by immunostainig on cryosections. Corneal barrier function was assessed in terms of permeability to carboxy fluorescein (CF). The distribution and expression of ZO-1, a known marker of tight junction, and reorganization of the perijunctional actomyosin ring (PAMR) were examined by immunofluorescence analysis. Although there were no significant differences between control and BAC-treated eyes in Schirmer scores, corneal fluorescein scores and the number of conjunctival MUC5AC staining cells, in vivo confocal microscopy revealed significant epithelial and stromal defects in all BAC-treated corneas. Moreover, BAC at 0.1% resulted in significant increases in central corneal thickness and endothelial CF permeability, compared with those in control eyes, and endothelial cell damage with dislocation of ZO-1 and disruption of PAMR. Topical application of BAC can quickly impair the whole cornea without occurrence of dry eye. A high concentration of BAC breaks down the barrier integrity of corneal endothelium, concomitant with the disruption of PAMR and remodeling of apical junctional complex in vivo.
Additive manufacturing of metals by employing continuous wave and short pulse lasers completely changes the way of modern industrial production. But the ultrafast laser has the superiority to short ...pulse laser and continuous wave laser in additive manufacturing. It has higher peak power, small thermal effect, high machining accuracy and low damage threshold. It can effectively perform additive manufacturing for special materials and improve the mechanical properties of parts. This article reviews the mechanism of the interaction between ultrafast laser and metal materials to rule the manufacturing processes. The current application of ultrafast laser on forming and manufacturing special materials, including refractory metals, transparent materials, composite materials and high thermal conductivity materials are also discussed. Among the review, the shortcomings and challenges of the current experimental methods are discussed as well. Finally, suggestions are provided for the industrial application of ultrashort pulse laser in the field of additive manufacturing in the future.
Glaucoma is the leading cause of irreversible blindness worldwide, and pathologically elevated intraocular pressure (IOP) is the major risk factor. Neuroprotection is one of the potential therapies ...for glaucomatous retinal damage. Intravitreal mesenchymal stem cell (MSC) transplantation provides a viable therapeutic option, and human umbilical cord- (hUC-) MSCs are attractive candidates for cell-based neuroprotection. Here, we investigated the ability of transplanted hUC-MSCs to survive and migrate within the vitreous cavity and their neuroprotective effects on chronic glaucomatous retina. For this, we developed a chronic ocular hypertension (COH) rat model through the intracameral injection of allogeneic Tenon’s fibroblasts. Green fluorescent protein-transduced hUC-MSCs were then injected into the vitreous cavity one week after COH induction. Results showed that a moderate IOP elevation lasted for two months. Transplanted hUC-MSCs migrated toward the area of damaged retina, but did not penetrate into the retina. The hUC-MSCs survived for at least eight weeks in the vitreous cavity. Moreover, the hUC-MSCs were efficient at decreasing the loss of retinal ganglion cells; retinal damage was attenuated through the inhibition of apoptosis. In this study, we have developed a novel COH rat model and demonstrated the prolonged neuroprotective potential of intravitreal hUC-MSCs in chronic glaucoma.
The purpose of this study was to explore the potential underlying mechanism of anti-vascular effects of peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate against corneal ...neovascularization (CNV) through the changes of lipid metabolism during CNV.
A suture-induced CNV model was established and the clinical indications were evaluated from day 1 to day 7. Treatments of vehicle and fenofibrate were performed for 5 days after suture and the CNV areas were compared among the groups. The eyeballs were collected for histological analysis, malondialdehyde (MDA) measurement, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining, western blot, quantitative real-time PCR (qRT-PCR) assays and immunohistochemical (IHC) staining to elucidate pathological changes and the underlying mechanism.
Lipi-Green staining and MDA measurement showed that lipid deposition and peroxidation were increased in the CNV cornea while the expression of long-chain acyl-coenzyme A synthetase 1 (ACSL1), carnitine palmitoyltransterase 1A(CPT1A) and medium-chain acyl-coenzyme A dehydrogenase (ACADM), which are key enzymes of fatty acid β-oxidation (FAO) and targeted genes of peroxisome proliferator-activated receptor alpha (PPARα) pathway, were decreased in CNV cornea. Fenofibrate suppressed lipid accumulation and peroxidation damage in the CNV cornea. Fenofibrate upregulated the expression levels of PPARα, ACSL1, CPT1A, and ACADM compared with vehicle group. IHC staining indicated that fenofibrate also decreased the expression of VEGFa, VEGFc, TNFα, IL1β and CD68.
Disorder of lipid metabolism may be involved in the formation of suture-induced CNV and fenofibrate played anti-neovascularization and anti-inflammatory roles on cornea by regulating the key enzymes of lipid metabolism and ameliorating lipid peroxidation damage of cornea through PPARα signaling pathway.
Meibomian gland dysfunction is the most frequent cause of evaporative dry eye, yet its underlying pathophysiology is unknown. To gain insight into this pathophysiology, we characterized the ...time-dependent tear film and ocular surface changes occurring in X-linked anhidrotic-hypohidrotic ectodermal dysplasia mice (Tabby), which lack the meibomian gland. These mice sequentially developed corneal epithelial defects, central corneal stromal edema, neovascularization, and pannus 8 to 16 weeks after birth. Aqueous tear secretion was normal, whereas tear break-up time and ex vivo tear evaporation times were all shortened. Corneal epithelial microvilli were less numerous, conjunctival goblet cell density was unaffected, and MUC5AC and MUC5B gene expression was increased. Markers of squamous metaplasia (cytokeratin 10 and small proline-rich protein 1B) were noticed in the corneal epithelium of Tabby mice as early as the fourth week. Taken together, the Tabby mouse is a relevant meibomian gland dysfunction-related dry eye model that may lead to a better understanding of how meibomian glands are related to ocular surface health. This model may also help with discovering novel drug options for treating evaporative dry eye.
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•Supplementation of L-NCFM and B-LBi07 regulate host metabolism and gut microbiota metabolism.•Supplementation of L-NCFM and B-LBi07 increase beneficial bacteria and inhibit harmful ...bacteria.•Supplementation of L-NCFM and B-LBi07 promote the functional maturation of gut bacterial community.•Key Metabolites are strongly correlated with the gut microbiota composition.
To investigate the effect of Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 (1:1) on microbiota composition and function, metabolism as well as microbiota-metabolite relationships of weaned rats, four groups of male Sprague-Dawley rats were orally supplemented with either probiotics (2.5 × 1010 cfu/kg, 5.0 × 1010 cfu/kg, 1.0 × 1011 cfu/kg) or vehicle (water) for 28 days. Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 treatment increased levels of glutamate, short chain fatty acids and ketone bodies, and decreased levels of choline, creatine and lactate. Levels of Rothia, Bifidobacterium, Jeotgalicoccus, Lactobacillus, Acinetobacter and Oligella were significantly increased, whereas Parabacteroides, Enterococcus and Candidatus Arthromitus were reduced. The PICRUSt analysis indicated Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 could promote the functional maturation of gut bacterial community. Strong correlations were observed between metabolites and Parabacteroides, Enterococcus, Candidatus Arthomitus, Bifidobacterium, Jeotgalicoccus, Lactobacillus and Acinetobacter. Collectively, supplementation of Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 helps promote the structure and functional maturation of intestinal microbiome in weaned rats.
In recent years, there have been increasing research interests in investigating the compression and ballistic responses of metal-ceramic hybrid structures, mainly making use of the synergistic ...effects of conventional metal honeycomb structures and infilled ceramic matrix materials. In this paper, a novel hybrid auxetic re-entrant metal-ceramic lattice is designed and manufactured to overcome the intrinsic conflicts between the strength and toughness of architected mechanical metamaterials, synergistic effects of auxetic re-entrant metal honeycombs and infilled ceramic materials are experimentally and numerically studied, and auxetic deformation features and failure modes are characterized with the digital image correlation (DIC) technique as well. It was found that (1) the infilled ceramic matrix of conventional honeycomb frames only endure longitudinal compression or impact loading along the external loading direction, while auxetic metal re-entrant honeycomb components endure both longitudinal and transverse loading due to the negative Poisson′s ratio effect and (2) the collaborative effects of infilled auxetics and the constraint frames’ hybrid structure dramatically moderate the stress concentration state and improve the impact resistance of single-phase ceramic materials. Our results indicate that the auxetic hybrid design exhibits promising industrial application potentials for blast protection engineering.
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