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1.
Front Surg ; 9: 814531, 2022.
Article in English | MEDLINE | ID: mdl-35419406

ABSTRACT

Lumbar disc herniation is among the common phenotypes of degenerative lumbar spine diseases, significantly affecting patients' quality of life. The practice pattern is diverse. Choosing conservative measures or surgical treatments is still controversial in some areas. For those who have failed conservative treatment, surgery with or without instrumentation is recommended, causing significant expenditures and frustrating complications, that should not be ignored. In the article, we performed a literature review and summarized the evidence by subheadings to unravel the cons of surgical intervention for lumbar disc herniation. There are tetrad critical issues about surgical treatment of lumbar disc herniation, i.e., favorable natural history, insufficient evidence in a recommendation of fusion surgery for patients, metallosis, and implant removal. Firstly, accumulating evidence reveals immune privilege and auto-immunity hallmarks of human lumbar discs within the closed niche. Progenitor cells within human discs further expand the capacity with the endogenous repair. Clinical watchful follow-up studies with repeated diagnostic imaging reveal spontaneous resolution for lumbar disc herniation, even calcified tissues. Secondly, emerging evidence indicates long-term complications of lumbar fusion, such as adjacent segment disease, pseudarthrosis, implant failure, and sagittal spinal imbalance, which get increasing attention. Thirdly, systemic and local reactions (metallosis) for metal instrumentation have been noted with long-term health concerns and toxicity. Fourthly, the indications and timing for spinal implant removal have not reached a consensus. Other challenging issues include postoperative lumbar stiffness. The review provided evidence from a negative perspective for surgeons and patients who attempt to choose surgical treatment. Collectively, the emerging underlying evidence questions the benefits of traditional surgery for patients with lumbar disc herniation. Therefore, the long-term effects of surgery should be closely observed. Surgical decisions should be made prudently for each patient.

2.
Liver Int ; 36(10): 1525-34, 2016 10.
Article in English | MEDLINE | ID: mdl-27028410

ABSTRACT

BACKGROUND: This study aimed to investigate the possible synergistic effects of lipid disorder with renin-angiotensin system (RAS) activation in non-alcoholic fatty liver disease (NAFLD). METHODS: Apolipoprotein E gene-knockout mice, angiotensin II (Ang II) type 1 receptor (AT1) gene-knockout mice and human hepatoblastoma cell line (HepG2) were used for experiments. Lipid accumulation was examined by Filipin staining and intracellular cholesterol quantitative assay. The gene and protein expression of molecules involved in RAS and low-density lipoprotein receptor (LDLr) pathway was examined by real-time PCR, immunofluorescent staining and Western blot. RESULTS: There was significantly increased expression of RAS components and extracellular matrix (ECM) in livers of high-fat-diet-fed apolipoprotein E gene-knockout mice compared with controls. Upregulation of RAS components was positively associated with increased plasma levels of lipid profile. The in vitro study further confirmed that cholesterol loading increased supernatant renin activity and Ang II level of HepG2 cells, accompanied by increased ECM production that was positively associated with increased expression of intracellular RAS components. Interestingly, Ang II treatment increased lipid accumulation in livers of C57BL/6 mice and HepG2 cells. Furthermore, Ang II treatment increased gene and protein expression of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), SREBP-2 and LDLr, which were mediated by enhanced SCAP/SREBP-2 complex translocation from endoplasmic reticulum to Golgi. However, LDLr pathway was accordingly downregulated in livers of AT1 gene-knockout C57BL/6 mice or in HepG2 cells treated by telmisartan. CONCLUSION: These findings demonstrate that lipid disorder and intrahepatic RAS activation synergistically accelerate NAFLD progression.


Subject(s)
Dyslipidemias/physiopathology , Extracellular Matrix/metabolism , Non-alcoholic Fatty Liver Disease/physiopathology , Receptors, LDL/metabolism , Renin-Angiotensin System , Angiotensin II/metabolism , Angiotensin II/pharmacology , Animals , Benzimidazoles/pharmacology , Benzoates/pharmacology , Cholesterol/metabolism , Diet, High-Fat , Hep G2 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lipid Metabolism/drug effects , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptor, Angiotensin, Type 1/genetics , Signal Transduction , Sterol Regulatory Element Binding Protein 2/genetics , Sterol Regulatory Element Binding Protein 2/metabolism , Telmisartan
3.
Am J Physiol Heart Circ Physiol ; 298(6): H1646-51, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20348217

ABSTRACT

Inflammatory stress accelerates the progression of atherosclerosis. Sirolimus, a new immunosuppressive agent, has been shown to have pleiotropic antiatherosclerotic effects. In this study we hypothesized that sirolimus inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR)-mediated cholesterol synthesis in human vascular smooth muscle cells (VSMCs) under inflammatory stress. Using radioactive assay, we demonstrated that sirolimus inhibited the increase of interleukin-1beta (IL-1beta)-induced cholesterol synthesis in VSMCs. Further studies showed that sirolimus inhibited both the HMGR gene and protein expression in VSMCs treated with or without IL-1beta. These effects were mediated by inhibiting the gene expression of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP-2 cleavage-activating protein (SCAP) as checked by real-time PCR, Western blot analysis, and confocal microscopy for the observation of decreased protein translocation of the SCAP/SREBP-2 complex from the endoplasmic reticulum (ER) to the Golgi. Insulin-induced gene-1 (Insig-1) is a key ER protein controlling the feedback regulation of HMGR at transcriptional and posttranscriptional levels. We demonstrated that sirolimus increased Insig-1 expression which may bind to the SCAP, preventing the exit of SCAP-SREBP complexes from the ER. The increased Insig-1 also accelerated HMGR protein degradation in VSMCs as shown by pulse-chase analysis. In conclusion, sirolimus inhibits cholesterol synthesis induced by inflammatory stress through the downregulation of HMGR expression and the acceleration of HMGR protein degradation. These findings may improve our understanding of the molecular mechanisms of the antiatherosclerosis properties of sirolimus.


Subject(s)
Cholesterol/metabolism , Immunosuppressive Agents/pharmacology , Inflammation/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Sirolimus/pharmacology , Acyl Coenzyme A/metabolism , Atherosclerosis/prevention & control , Cells, Cultured , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Coronary Vessels/pathology , Endoplasmic Reticulum/metabolism , Golgi Apparatus/metabolism , Humans , Inflammation/pathology , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Muscle, Smooth, Vascular/pathology , Sterol Regulatory Element Binding Protein 2/metabolism
4.
Hepatology ; 48(3): 770-81, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18752326

ABSTRACT

UNLABELLED: The prevailing theory in non-alcoholic fatty liver disease (NAFLD) is the "two-hit" hypothesis. The first hit mainly consists of lipid accumulation, and the second is subsequent systemic inflammation. The current study was undertaken to investigate whether inflammatory stress exacerbates lipid accumulation in liver and its underlying mechanisms. We used interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulation in human hepatoblastoma cell line (HepG2) cells and primary hepatocytes in vitro, and casein injection in apolipoprotein E knockout mice in vivo to induce inflammatory stress. The effects of inflammatory stress on cholesterol accumulation were examined by histochemical staining and a quantitative intracellular cholesterol assay. The gene and protein expressions of molecules involved in cholesterol trafficking were examined by real-time polymerase chain reaction (PCR) and western blot. Cytokine production in the plasma of apolipoprotein E knockout mice was measured by enzyme-linked immunosorbent assay. Our results showed that inflammatory stress increased cholesterol accumulation in hepatic cells and in the livers of apolipoprotein E knockout mice. Further analysis showed that inflammatory stress increased the expression of low-density lipoprotein (LDL) receptor (LDLr), sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), and SREBP-2. Confocal microscopy showed that IL-1beta increased the translocation of SCAP/SREBP-2 complex from endoplasmic reticulum (ER) to Golgi in HepG2 cells, thereby activating LDLr gene transcription. IL-1beta, TNF-alpha, and systemic inflammation induced by casein injection also inhibited expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and liver X receptor-alpha (LXRalpha). This inhibitory effect may cause cholesterol efflux reduction. CONCLUSION: Inflammatory stress up-regulates LDLr-mediated cholesterol influx and down-regulates ABCA1-mediated cholesterol efflux in vivo and in vitro. This may exacerbate the progression of NAFLD by disrupting cholesterol trafficking control, especially during the second hit phase of liver damage.


Subject(s)
Cholesterol/metabolism , Fatty Liver/metabolism , Hepatocytes/metabolism , Inflammation/metabolism , Lipid Metabolism/physiology , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Apolipoproteins E/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Disease Models, Animal , Fatty Liver/pathology , Hepatocytes/drug effects , Hepatocytes/pathology , Humans , Inflammation/chemically induced , Inflammation/pathology , Interleukin-1beta/adverse effects , Lipid Metabolism/drug effects , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orphan Nuclear Receptors , PPAR alpha/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/metabolism , Tumor Necrosis Factor-alpha/adverse effects
5.
Transplantation ; 84(8): 1029-36, 2007 Oct 27.
Article in English | MEDLINE | ID: mdl-17989609

ABSTRACT

BACKGROUND: Sirolimus is a potent immunosuppressive agent, which is associated with dyslipidemia in clinical transplantation. The present study was undertaken to investigate the potential hepatocyte mechanisms by which sirolimus causes dyslipidemia. METHODS: Using both a quantitative assay of intracellular cholesterol and an [3H]-labeled cholesterol efflux assay, we studied the effect of sirolimus on cholesterol accumulation and cholesterol efflux in HepG2 cells in the absence or presence of inflammatory stress induced by interleukin-1beta. The gene and protein expression of molecules involved in cholesterol homeostasis were examined by real-time reverse-transcription polymerase chain reaction and Western blotting. RESULTS: Sirolimus inhibited low-density lipoprotein (LDL) receptor (LDLr)-mediated cholesterol ester accumulation induced by interleukin-1beta in HepG2 cells. This inhibitory effect was mediated by down-regulation of sterol regulatory element-binding proteins (SREBP) cleavage activating protein (SCAP) and SREBP-2 mRNA expression. Using confocal microscopy, we demonstrated that sirolimus reduced translocation of SCAP-SREBP2 complex from endoplasmic reticulum to Golgi for activation, thereby inhibiting LDLr gene transcription. Reduction of LDLr in the liver may result in a delay of LDL-cholesterol clearance from circulation causing an increase of plasma cholesterol concentration. Furthermore, sirolimus increased cholesterol efflux mediated by adenosine triphosphate-binding cassette transporter A1 gene expression by increasing peroxisome proliferator-activated receptor-alpha and liver X receptor-alpha gene and protein expression. Increased cholesterol efflux from HepG2 cells may increase high-density lipoprotein cholesterol level and also contribute to apolipoprotein B lipoprotein formation by enhancing transfer of high-density lipoprotein cholesterol to apolipoprotein B lipoproteins. CONCLUSIONS: This study demonstrates that the increase of LDL cholesterol by sirolimus is partly due to the reduction of LDLr on hepatocytes.


Subject(s)
Cholesterol, LDL/metabolism , Dyslipidemias/chemically induced , Hepatocytes/drug effects , Immunosuppressive Agents/pharmacology , Receptors, LDL/antagonists & inhibitors , Sirolimus/pharmacology , Cell Line , Dyslipidemias/metabolism , Endoplasmic Reticulum/chemistry , Endoplasmic Reticulum/metabolism , Golgi Apparatus/chemistry , Golgi Apparatus/metabolism , Hepatocytes/metabolism , Homeostasis/drug effects , Humans , Immunosuppressive Agents/adverse effects , Intracellular Signaling Peptides and Proteins/analysis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/analysis , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/metabolism , Protein Transport , RNA, Messenger/analysis , RNA, Messenger/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Sirolimus/adverse effects , Sterol Regulatory Element Binding Protein 2/analysis , Sterol Regulatory Element Binding Protein 2/antagonists & inhibitors , Sterol Regulatory Element Binding Protein 2/metabolism
6.
Am J Physiol Heart Circ Physiol ; 292(6): H2721-8, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17322416

ABSTRACT

Sirolimus is a potent immunosuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1 beta. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1 beta, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthermore, the effect of sirolimus on cholesterol efflux from VSMCs in the presence or absence of IL-1 beta was also investigated using [(3)H] cholesterol efflux. Finally, we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1 beta possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1 beta. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1 beta. We further confirmed that sirolimus inhibited mRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-alpha, IL-8, and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs.


Subject(s)
Atherosclerosis/prevention & control , Cardiovascular Agents/pharmacology , Cholesterol/metabolism , Inflammation/prevention & control , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Sirolimus/pharmacology , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Atherosclerosis/genetics , Atherosclerosis/metabolism , Azo Compounds , Cardiovascular Agents/therapeutic use , Cells, Cultured , Coloring Agents , Coronary Vessels/cytology , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Cytokines/genetics , Cytokines/metabolism , Dose-Response Relationship, Drug , Gene Expression/drug effects , Homeostasis/drug effects , Humans , Inflammation/genetics , Inflammation/metabolism , Interleukin-1beta/metabolism , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , RNA, Messenger/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Sirolimus/therapeutic use , Staining and Labeling/methods
7.
Arterioscler Thromb Vasc Biol ; 26(5): 1150-5, 2006 May.
Article in English | MEDLINE | ID: mdl-16543490

ABSTRACT

OBJECTIVE: Although inflammation is a recognized feature of atherosclerosis, the impact of inflammation on cellular cholesterol homeostasis is unclear. This study focuses on the molecular mechanisms by which inflammatory cytokines disrupt low-density lipoprotein (LDL) receptor regulation. METHODS AND RESULTS: IL-1beta enhanced transformation of vascular smooth muscle cells into foam cells by increasing uptake of unmodified LDL via LDL receptors and by enhancing cholesterol esterification as demonstrated by Oil Red O staining and direct assay of intracellular cholesterol concentrations. In the absence of IL-1beta, a high concentration of LDL decreased LDL receptor promoter activity, mRNA synthesis and protein expression. However, IL-1beta enhanced LDL receptor expression, overriding the suppression usually induced by a high concentration of LDL and inappropriately increasing LDL uptake. Exposure to IL-1beta also caused overexpression of the sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), and enhanced its translocation from the endoplasmic reticulum to the Golgi, where it is known to cleave SREBP, thereby enhancing LDL receptor gene expression. CONCLUSIONS: These observations demonstrate that IL-1beta disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam cell formation. The implication of these findings is that inflammatory cytokines may contribute to intracellular LDL accumulation without previous modification of the lipoprotein.


Subject(s)
Gene Expression Regulation/drug effects , Interleukin-1/pharmacology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Receptors, LDL/genetics , Cells, Cultured , Endoplasmic Reticulum/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Lipoproteins, LDL/metabolism , Membrane Proteins/metabolism , Promoter Regions, Genetic , Sterol O-Acyltransferase/genetics , Sterol O-Acyltransferase/metabolism , Sterol Regulatory Element Binding Proteins/metabolism
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