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regulates the p62 expression and restrains the inflammatory response in colitis. Our result suggests that targeting SETD8 may be a promising therapy for IBD.Cationic polymers dynamically complex DNA into complexes (polyplexes). So, upon dilution, polyplexes easily dissociate and lose transfection ability, limiting their in vivo systemic gene delivery. Herein, it is found that polyplex's stability and endocytosis pathway determine its transfection dose-dependence. The polyplexes of hydrophilic polycations have dose-dependent integrity and lysosome-trafficking endocytosis; at low doses, most of these polyplexes dissociate, and the remaining few are internalized and trapped in lysosomes, abolishing their transfection ability. In contrast, the polyplexes of the polycations with optimal hydrophobicity remain integrated even at low concentrations and enter cells via macropinocytosis directly into the cytosol evading lysosomes, so each polyplex can accomplish its infection process, leading to dose-independent DNA transfection like viral vectors. Furthermore, the tuned hydrophobicity balancing the affinity of anionic poly(γ-glutamic acid) (γ-PGA) to the polyplex surface enables γ-PGA to stick on the polyplex surface as a shielding layer but peel off on the cell membrane to release the naked polyplexes for dose-independent transfection. These findings may provide guidelines for developing polyplexes that mimick a viral vector's dose-independent transfection for effective in vivo gene delivery.Nonhealing wounds in diabetes remain a global clinical and research challenge. Exosomes are primary mediators of cell paracrine action, which are shown to promote tissue repair and regeneration. In this study, we investigated the effects of serum derived exosomes (Serum-Exos) on diabetic wound healing and its possible mechanisms. Serum-Exos were isolated from blood serum of normal healthy mice and identified by transmission electron microscopy and western blot. The effects of Serum-Exos on diabetic wound healing, fibroblast growth and migration, angiogenesis and extracellular matrix (ECM) formation were investigated. Our results showed that the isolated Serum-Exos exhibited a sphere-shaped morphology with a mean diameter at 150 nm, and expressed classical markers of exosomes including HSP70, TSG101, and CD63. Treatment with Serum-Exos elevated the percentage of wound closure and shortened the time of healing in diabetic mice. GLPG1690 mouse Mechanistically, Serum-Exos promoted granulation tissue formation and increased the expression of CD31, fibronectin and collagen-ɑ in diabetic mice. Serum-Exos also promoted the migration of NIH/3T3 cells, which was associated with increased expression levels of PCNA, Ki67, collagen-α and fibronectin. In addition, Serum-Exos enhanced tube formation in human umbilical vein endothelial cells and induced the expression of CD31 at both protein and messenger RNA levels. Collectively, our results suggest that Serum-Exos may facilitate the wound healing in diabetic mice by promoting angiogenesis and ECM formation, and show the potential application in treating diabetic wounds.
Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.
We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.
We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.
Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.High-grade gliomas (HGGs) are aggressive, treatment-resistant, and often fatal human brain cancers. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild-type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication-competent avian sarcoma-leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural-like gliomas led tt constitutive NF-κB pathway activation and plasminogen activator inhibitor-1 overexpression.Patients presenting with chronic wounds in venous insufficiency often represent a challenge, like other conditions, like lymphatic impairment, may complicate the wound healing process. The purpose of this report is to highlight how the treatment of lymphatic impairment may be beneficial in patients affected by chronic ulcers with concomitant venous insufficiency. We present the case of a 78-year-old woman affected by chronic venous insufficiency (CVI) with long-lasting ulcers secondary to sclerosing agents treatment for varicose veins. The patient's condition was refractory to both conservative and surgical treatment. Since the patient also presented with severe lymphorrhea, with a significant amount of daily secretion, ICG-lymphography was performed subcutaneously, to visualize the pathway of lymphatic drainage and leakage. It also allowed marking on the skin the exact location of lymphatic vessels distally to the wound area. Hence, two lymphatico-venous anastomoses were performed between the two major collecting lymphatic vessels and two subcutaneous veins of adequate size.
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