Abnormal lipid-mediated hepatic inflammatory-immune dysfunction and chronic low grade inflammation play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophage polarization is an important mechanism for the regulation of inflammatory response. Since PPAR-γ has emerged as a master regulator of macrophage polarization, we aimed to investigate the lipid-induced macrophage/Kupffer cell polarization in vivo and in vitro, and explore the association between PPAR-γ activity and macrophages M1/M2 polarization shifting. Here we showed that long-term high-fat diet increased Kupffer cells content with M1-predominant phenotype and increasing production of pro-inflammatory cytokines. Saturated fatty acids polarized Kupffer cells/macrophages to an M1-predominant phenotype while n-3 PUFA polarized Kupffer cells/macrophages to an M2 phenotype, which was associated with activation of NF-κB signal pathway and PPAR-γ respectively. Furthermore, up-regulation of PPAR-γ shifted lipid-induced macrophages polarization from M1-predominant phenotype to M2 phenotype. Macrophages polarization switch was associated with the interaction between PPAR-γ and NF-κBp65 signal pathway. Rosiglitazone restored high-fat diet-induced imblance of Kupffer cells M1/M2 polarization and alleviated hepatic steatosis as well as local pro-inflammatory response. These findings suggest that manipulation of PPAR-γ activity has the potential to balance lipid-induced M1/M2 macrophage/Kupffer cell polarization, and leading to prevent the development of NAFLD.
"Cone dystrophy with supernormal rod electroretinogram (ERG)" is an autosomal recessive disorder that causes lifelong visual loss combined with a supernormal ERG response to a bright flash of light. We have linked the disorder to a 0.98-cM (1.5-Mb) region on chromosome 9p24, flanked by rs1112534 and rs1074449, using homozygosity mapping in one large consanguineous pedigree. Analysis of one gene within this region, KCNV2, showed a homozygous nonsense mutation. Mutations were also found in 17 alleles of 10 other unrelated families with the same disorder. In situ hybridization demonstrated KCNV2 expression in human rod and cone photoreceptors. The precise function of KCNV2 in human photoreceptors remains to be determined, although this work suggests that mutations might perturb or abrogate I(KX), the potassium current within vertebrate photoreceptor inner segments, which has been shown to set their resting potential and voltage response.
Dietary microRNAs have been shown to be absorbed by mammals and regulate host gene expression, but the absorption mechanism remains unknown. Here, we show that SIDT1 expressed on gastric pit cells in the stomach is required for the absorption of dietary microRNAs. SIDT1-deficient mice show reduced basal levels and impaired dynamic absorption of dietary microRNAs. Notably, we identified the stomach as the primary site for dietary microRNA absorption, which is dramatically attenuated in the stomachs of SIDT1-deficient mice. Mechanistic analyses revealed that the uptake of exogenous microRNAs by gastric pit cells is SIDT1 and low-pH dependent. Furthermore, oral administration of plant-derived miR2911 retards liver fibrosis, and this protective effect was abolished in SIDT1-deficient mice. Our findings reveal a major mechanism underlying the absorption of dietary microRNAs, uncover an unexpected role of the stomach and shed light on developing small RNA therapeutics by oral delivery.
Pseudo-Continuous Arterial Spin Labeling (PCASL) can be used to generate non-contrast MR angiograms of the cerebrovascular structures. Previously described PCASL-based angiography techniques were limited to 2D projection images or relatively low-resolution 3D imaging due to long aquisition time. This work proposes a new PCASL-based 3D MRA method that uses an accelerated 3D radial acquisition technique (VIPR, spoiled gradient echo) as the readout. Benefiting from the sparsity provided by PCASL and noise-like artifacts of VIPR, this new method is able to obtain sub-millimeter 3D isotropic resolution and whole head coverage with a 8-minute scan. Intracranial angiography feasibility studies in healthy (N=5) and diseased (N=5) subjects show reduced saturation artifacts in PCASL-VIPR compared to a standard Time-of-Flight protocol. These initial results show great promise for PCASL-VIPR for static, dynamic, and vessel selective 3D intracranial angiography.
Purpose To develop a novel dynamic 3D non-contrast MR angiography technique which combines dynamic Pseudo-continuous Arterial Spin Labeling (dynamic PCASL), accelerated 3D radial sampling (VIPR), and time-of-arrival (TOA) mapping to provide quantitative assessment of arterial flow. Materials and Methods Digital simulations were performed to investigate the effects of acquisition scheme and sequence parameters on image quality and TOA mapping fidelity. Five patients with vascular malformations (AVM=3, DAVF=2) were scanned and the images were compared to DSA for the ability to identify the arterial supply, AVM location, nidus size and venous drainage. Results Digital simulations demonstrated reduced image artifacts and improved TOA accuracy utilizing radial acquisition over Cartesian. TOA mapping accuracy is more sensitive to sampling window length than time spacing. Dynamic PCASL MRA depicted 7 of 8 arterial pedicles, and accurately measured the AVM nidus size when the nidus was compact. The venous drainage in the AVM patients was not consistently visualized. Conclusion Dynamic 3D PCASL-VIPR with TOA mapping is able to acquire both high temporal and spatial resolution inflow dynamics that could improve diagnosis of high flow intracranial vascular diseases.
Background and Aim Chronic inflammation links closely to insulin resistance and lipid metabolism in nonalcoholic fatty liver disease (NAFLD). Macrophage M1 activation plays an important role in the initiation and continuing of pro‐inflammatory response of NAFLD. Our study was to investigate whether macrophage M1/M2 polarization switching would affect hepatic inflammation and lipid metabolism through modulation of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) activity in vivo and in vitro. Methods RAW264.7 macrophages were treated with different fatty acids, and cell culture supernatants were collected to prepare conditioned media (CM). Different co‐culture systems between primary hepatocytes and CM from macrophages were established. A PPAR‐γ agonist or antagonist was administered to regulate PPAR‐γ activity and macrophage polarization. M1/M2 phenotype markers, inflammatory signaling pathway, and lipid‐related genes expression were determined. Wild‐type C57BL/6 mice were fed a high‐fat diet to induce NAFLD and given rosiglitazone to regulate PPAR‐γ activity in vivo. Results Saturated fatty acids induced M1‐polarized macrophages while polyunsaturated fatty acids induced M2‐polarized macrophages. M1‐polarized macrophages significantly promoted lipid synthesis and accumulation in primary hepatocytes through upregulation of a toll‐like receptor 4 (TLR4)/NF‐κB signaling pathway. The PPAR‐γ agonist made lipid‐induced M1‐polarized macrophages switch to an M2‐predominant phenotype, while PPAR‐γ antagonist had the opposite effect. Macrophage polarization shifting subsequently affected lipid metabolism in primary hepatocytes. Administration of rosiglitazone improved high‐fat diet induced hepatic steatosis and lipid metabolism through reducing hepatic TLR4/NF‐κB expression and M1‐polarized Kupffer cells. Conclusions Lipid‐induced macrophage M1 polarization promoted hepatic lipid metabolism. Modulation of PPAR‐γ activity could shift macrophage polarization and subsequently affect lipid metabolism. Upregulation of the TLR4/NF‐κB signaling pathway is closely linked to dysregulated lipid metabolism in NAFLD.
Curcumin is a natural polyphenol with powerful antioxidant and anti-inflammatory properties. The present study evaluated the protective effect of curcumin on myocardial injury in rats as well as the mechanisms underlying these effects, and examined the expression of nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor-γ (PPAR-γ) and B-cell leukemia/lymphoma-2 (Bcl-2) following myocardial infarction. A rat model of myocardial infarction was successfully established. Hematoxylin and eosin staining showed cellular atrophy and hyperchromatic cytoplasm in the myocardial infarction area. The myocardial cells displayed lysis and breakage of cardiac muscle fibers, karyopyknosis and karyorrhexis associated with infiltration of inflammatory cells and proliferation of fibrous tissue. Curcumin treatment at a dosage of 150 mg/kg/body weight resulted in an increase in surviving cells, fewer apoptotic cells, decreased proliferation of fibrous tissue and reduced infiltration of inflammatory cells, though necrosis was still present compared with the rats without curcumin treatment. The immunohistochemical assay demonstrated that curcumin treatment inhibited the expression of NF-κB, but increased the expression of PPAR-γ. The results of the reverse transcription-polymerase chain reaction indicated that curcumin treatment significantly increased the mRNA expression levels of Bcl-2 (P<0.01). Therefore, curcumin antagonizes cardiomyocyte apoptosis and inhibits inflammatory cell infiltration following myocardial infarction, which may be associated with its inhibitory effects on the expression of NF-κB, and activating effects on the expression of PPAR-γ and Bcl-2 in myocardial cells. Curcumin may be useful in clinical practice for saving more living heart muscle in the area of myocardial infarction and improving cardiac function following the elective opening of obstructed coronary arteries.
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