Analysis of soft tissue hardness changes in cervical lymph node enlargement based on multimodal ultrasound parameters and lipid metabolism regulation

Apolipoprotein E (apo E) deficiency (or its abnormalities in humans) is associated with a series of pathological conditions including dyslipidemia, atherosclerosis, Alzheimer's disease, and shorter life span. The purpose of this study was to characterize these conditions in apo E-deficient C57BL/6J mice and relate them to human disorders. Deletion of apo E gene in mice is associated with changes in lipoprotein metabolism [plasma total cholesterol (TC) (>+400%), HDL cholesterol (-80%), HDL/TC, and HDL/LDL ratios (-93% and -96%, respectively), esterification rate in apo B-depleted plasma (+100%), plasma triglyceride (+200%), hepatic HMG-CoA reductase activity (-50%), hepatic cholesterol content (+30%)], decreased plasma homocyst(e)ine and glucose levels, and severe atherosclerosis and cutaneous xanthomatosis. Hepatic and lipoprotein lipase activities, hepatic LDL receptor function, and organ antioxidant capacity remain unchanged. Several histological/immunohistological stainings failed to detect potential markers for neurodegenerative disease in the brain of 37-wk-old male apo E-KO mice. Apo E-KO mice may have normal growth and development, but advanced atherosclerosis and xanthomatosis may indirectly reduce their life span. Apo E plays a crucial role in regulation of lipid metabolism and atherogenesis without affecting lipase activities, endogenous antioxidant capacity, or appearance of neurodegenerative markers in 37-wk-old male mice.

Early investigations into the mechanism by which some sources of dietary fiber exert their hypocholestermic effects centered on changes in steroid excretion brought about by adsorption of bile salts and bile acids by some component(s) of dietary fiber (Story and Kritchevsky, 1976; Story, 1980). Subsequent examination of the relationship between the magnitude of change in steroid excretion and in serum cholesterol indicated that this single phenomenon could not explain the range of effects observed with various dietary fiber-related materials (Kay and Truswell, 1980; Story, 1980). Change in lipoprotein metabolism has emerged as an additional explanation for the involvement of dietary fiber in regulation of lipid metabolism. The association of the levels of low-density lipoproteins (LDL) with increased risk of atherosclerotic heart disease and high-density lipoproteins (HDL) with reduced risk, and the importance of these lipoproteins in regulation of all phases of lipid metabolism, have made examination of the effects of dietary fiber on these variables especially interesting.

Interference with the enterohepatic circulation leads to changes in plasma lipoprotein metabolism. Thus, increased bile acid synthesis (such as after cholestyramine therapy or biliary diversion) stimulates hepatic triglyceride production and increases the number of low density lipoprotein (LDL) receptors in the liver. However, treatment with chenodeoxycholic acid reduces triglyceride production and appears to reduce LDL catabolism. Ursodeoxycholic acid therapy, which has minor effects on bile acid synthesis, results in relatively minor changes in lipoprotein metabolism. A tendency for lowered LDL cholesterol levels may be related to the fact that ursodeoxycholic acid interferes with the enterohepatic circulation of the normal bile acids, particularly when administered at a high dosage.

The changes in lipoprotein metabolism which follow the ingestion of a large fat load have been well described. The hypothesis was tested that similar changes in lipoprotein metabolism would occur after a relatively normal meal. Plasma and lipoprotein triacylglycerol, cholesterol and apolipoprotein concentrations were determined in twenty subjects (ten female) given a mixed meal containing approximately one-third of the daily intake of major nutrients in the typical Western diet. Fasting plasma triacylglycerol concentrations (range 0.38-2.70 mm/l) and the postprandial rise in plasma triacylglycerol varied considerably between subjects and were significantly associated (P < 0.01). The rise in plasma triacylglycerol corresponded to marked increases in the triacylglycerol concentration of the triacylglycerol-rich lipoproteins (TRL; chylomicrons and very-low-density lipoproteins). TRL cholesterol also increased after the meal. An increase in high-density-lipoprotein (HDL)-triacylglycerol following the meal was accompanied by a decrease in HDL-cholesterol concentration, presumably due to the action of the cholesteryl-ester transfer protein. The increases in HDL-triacylglycerol and in TRL-cholesterol were correlated with the postprandial rise in triacylglycerol in the TRL (P < 0.01). We conclude that potentially adverse changes occur in both triacylglycerol-rich and high-density lipoproteins following a typical mixed meal, as they do after large fat loads. The changes are exaggerated in those subjects with greater fasting plasma triacylglycerol concentrations.

BackgroundTissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFβ1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling.ObjectivesWe examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling.MethodsHuman cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFβ1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis.ResultsTGFβ1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFβ1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations.ConclusionsLMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.

Although tumor cell heterogeneity between the tumor center (TC) and invasion front (IF) of oral squamous cell carcinoma (OSCC) is well documented, the morphological, molecular, and functional characteristics of cancer-associated fibroblasts (CAFs) in these regions remain poorly understood. We examined hematoxylin and eosin (H&E)-stained OSCC sections to assess CAF morphology and correlation with patient prognosis. We then isolated paired CAFs from the tumor center (CAFTC) and invasion front (CAFIF) of four OSCC patients and compared their ECM-remodeling activity and pro-tumorigenic effects on OSCC cells. Furthermore, RNA sequencing identified differentially expressed genes between CAFTC and CAFIF. Finally, based on RNA-seq findings, we knocked down hyaluronan synthase 1 (HAS1) in CAFIF to evaluate its role in extracellular matrix (ECM) remodeling and tumor invasion. Compared to CAFTC, CAFIF exhibited a plump cell morphology and were associated with shorter disease-free survival. Functionally, CAFIF showed higher ECM-remodeling activity and more effective ability for promoting OSCC invasion and lymph node metastasis than CAFTC. RNA-seq identified HAS1 was significantly upregulated in CAFIF, promoting hyaluronic acid (HA) production and ECM remodeling. HAS1 knockdown in CAFIF diminished ECM remodeling and attenuated the ability of CAFIF to promoting OSCC invasion. CAFIF with plump cell morphology showed pro-invasive abilities, driven in part by HAS1 overexpression and ECM remodeling, suggesting that targeting HAS1-driven ECM remodeling could be a promising therapeutic strategy.

Cardiovascular disease (CVD) is ranked as the number one cause of death worldwide. The causes of CVD are defined by interplay between genetics and environmental factors; this contributes to the complexity of the pathophysiology of CVD. In spite of the advancement in medical science and drug discovery, the prevalence of CVD is still on the rise. The most important environmental factor in the pathogenesis of CVD is nutrition, especially the role of dietary fats. There are numerous reports supporting the cardioprotective effects of omega (n)-3 polyunsaturated fatty acids (PUFAs); however, there are also controversial reports. Given the complexity and physiological variation of the human population, it is pertinent to consider the various factors that could potentially affect the metabolism and hence the health benefits of n-3 PUFA before a strong recommendation can be made. The focus of this chapter is on the cardioprotective effects of n-3 PUFA, with particular emphasis on the regulation of lipid and lipoprotein metabolism, and factors such as age, sex and epigenetic modification that could potentially affect the health benefits of n-3 PUFA. This chapter also summarizes the emerging paradigm of the connection between CVD and neuropsychiatric disorders; it presents the propensity of n-3 PUFA to facilitate a therapeutic connection between these two diseases through a common pathway of neurotrophin signalling.

Dietary fish oil is considered beneficial in the management of cardiovascular diseases. The hypotriglyceridemic effects of fish oil supplementation are mediated by the regulation of lipid metabolism. n-3 polyunsaturated fatty acids (PUFA) present in fish oil can alter the transcription of genes involved in lipid synthesis, oxidation and transport. Gene regulation at the transcriptional level involves several nuclear receptors and transcription factors, including peroxisome proliferator activated receptors, sterol-regulatory element binding protein, liver X-receptors, farnesoid X receptors and hepatocyte nuclear factor-4α. Differential regulation of the transcription factors by n-3 PUFA specifically regulates lipid metabolism in a tissue-specific manner and is dependent on the genetic background. The ability of n-3 PUFA to regulate transcription factors makes them a potential nutritional tool to treat certain lipid disorders. n-3 PUFA derivatives need to be designed with optimal effects as pharmacological ...

Roughly 10% of genes of the human genome, among them all 48 human nuclear receptors (NR), are druggable, meaning that the function of their gene products can be modulated by small molecules. The classes NR1I/NR1H comprise molecules which initially have been described as orphan NR. They are now recognized as lipid and drug sensing molecules. Unlike PPARs belonging to the NR1C subfamily which are activated by triglyceride derivatives Constitutive Androstane Receptor Receptor (CAR), Pregnane-X-Receptor (PXR), Farnesoid Receptor (FXR) and Liver-X-Receptor are activated by cholesterol derivatives, bile acids, steroids and bilirubin. A common functional feature of these NRs is induction of a wide range of detoxifying enzymes. NRs are intimately involved in regulation of lipid metabolism and/or they contribute to liver protection. LXRs activated by oxysterols play the most prominent role in regulation of metabolic disease. LXRs have been described as regulators of lipogenesis, of cholesterol and glucose homeostasis and of anti-inflammatory processes, all representing specific features of the metabolic syndrome. FXR upon activation by chenodesoxycholic acid participates in regulation of lipid, lipoprotein and glucose metabolism as well as in hepatic regeneration and hepatoprotection. PXR is activated by pregnane derivatives and together with CAR and FXR guides cholesterol and bile acid homeostasis. Because of the functional link of these NRs to disease they represent valuable drug targets, inlcuding for plant derived natural compounds. The paper presented here will summarize data on plant secondary metabolites modulating the function of these lipid sensos in relation to specific aspects of the metabolic syndrome. Keywords: metabolic syndrome, lipid sensing, nuclear receptor, FXR, LXR, PXR, CAR

Lymph node (LN) metastasis is an important prognostic parameter in breast carcinoma, a crucial site for tumour–immune cell interaction and a gateway for further dissemination of tumour cells to other metastatic sites. To gain insight into the underlying molecular changes from the pre-metastatic, via initial colonisation to the fully involved LN, we reviewed transcriptional research along the evolving microenvironment of LNs in human breast cancers patients. Gene expression studies were compiled and subjected to pathway-based analyses, with an emphasis on immune cell-related genes. Of 366 studies, 14 performed genome-wide gene expression comparisons and were divided into six clinical-biological scenarios capturing different stages of the metastatic pathway in the LN, as follows: metastatically involved LNs are compared to their patient-matched primary breast carcinomas (scenario 1) or the normal breast tissue (scenario 2). In scenario 3, uninvolved LNs were compared between LN-positive patients and LN-negative patients. Scenario 4 homed in on the residual uninvolved portion of involved LNs and compared it to the patient-matched uninvolved LNs. Scenario 5 contrasted uninvolved and involved LNs, whilst in scenario 6 involved (sentinel) LNs were assessed between patients with other either positive or negative LNs (non-sentinel).Gene lists from these chronological steps of LN metastasis indicated that gene patterns reflecting deficiencies in dendritic cells and hyper-proliferation of B cells parallel to tumour promoting pathways, including cell adhesion, extracellular matrix remodelling, cell motility and DNA repair, play key roles in the changing microenvironment of a pro-metastatic to a metastatically involved LN. Similarities between uninvolved LNs and the residual uninvolved portion of involved LNs hinted that LN alterations expose systemic tumour-related immune responses in breast cancer patients. Despite the diverse settings, gene expression patterns at different stages of metastatic colonisation in LNs were recognised and may provide potential avenues for clinical interventions to counteract disease progression for breast cancer patients.

Posttranscriptional regulation of lipid metabolism by non-coding RNAs and RNA binding proteins

Discovering new therapeutic interventions to treat lipid and lipoprotein disorders is of great interest and the discovery of autophagy as a regulator of lipid metabolism has opened up new avenues for targeting modulators of this pathway. Autophagy is a degradative process that targets cellular components to the lysosome and recent studies have indicated a role for autophagy in regulating hepatic lipid metabolism (known as lipophagy) as well as lipoprotein assembly. Autophagy directly targets apolipoprotein B-100 (apoB100), the structural protein component of very low-density lipoproteins (VLDLs), and further targets lipid droplets (LDs), the cellular storage for neutral lipids. Autophagy thus plays a complex and dual role in VLDL particle assembly by regulating apoB100 degradation as well as aiding the maturation of VLDL particles by hydrolyzing lipid from LDs. The purpose of this article is to review our current understanding of molecular and cellular mechanisms mediating authophagic control of hepatic lipid biogenesis and VLDL production as well as dysregulation in insulin resistance and dyslipidemia.

BackgroundPeroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. The aim of the present study was to characterize the interrelationship between PPARα and CREB3L3 in regulating hepatic gene expression. Male wild-type, PPARα−/−, CREB3L3−/− and combined PPARα/CREB3L3−/− mice were subjected to a 16-h fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples.ResultsUnder conditions of overnight fasting, the effects of PPARα ablation and CREB3L3 ablation on plasma triglyceride, plasma β-hydroxybutyrate, and hepatic gene expression were largely disparate, and showed only limited interdependence. Gene and pathway analysis underscored the importance of CREB3L3 in regulating (apo)lipoprotein metabolism, and of PPARα as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARα and CREB3L3. By contrast, a strong interaction between PPARα and CREB3L3 ablation was observed during ketogenic diet feeding. Specifically, the pronounced effects of CREB3L3 ablation on liver damage and hepatic gene expression during ketogenic diet were almost completely abolished by the simultaneous ablation of PPARα. Loss of CREB3L3 influenced PPARα signalling in two major ways. Firstly, it reduced expression of PPARα and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARα was markedly activated by loss of CREB3L3.ConclusionsThese data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARα. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARα and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status.

Periprandial regulation of lipid metabolism in insulin-treated diabetes mellitus

Dyslipidemia and nephrotic syndrome: Recent advances