The aim of this study was to document the effect of hesperidin on the key enzyme activities of carbohydrate metabolism, lipid profile, and membrane-bound adenosine triphosphatases (ATPases) during 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis. Hesperidin has been reported to have multiple biological properties. Breast cancer was induced by single dose of DMBA (20 mg/kg body weight (bw)). The results revealed that there was a significant increase in the activities of hexokinase, phosphoglucoisomerase, and aldolase and a concomitant decrease in the activities of glucose-6-phosphatase and fructose-1,6-diphosphatase in cancer-induced animals. The activities of ATPases were found to be decreased both in erythrocyte membrane and in the liver of mammary cancer-bearing animals. The lipid profiles such as total cholesterol, free cholesterol, phospholipids, triglycerides, and free fatty acids significantly increased and in contrast the ester cholesterol in plasma was found to be decreased, whereas it was found to be elevated in the liver of cancer-bearing groups. The altered levels of the above-mentioned biochemical parameters in cancer-bearing animals were significantly ameliorated by the administration of hesperidin at the dosage of 30 mg/kg bw for 45 days. The histopathological analysis of breast and liver tissues were well supported the modulatory property of hesperidin, and this might be associated with normalizing the gluconeogenesis process, stabilization of cell membranes, and modulation of lipid biosynthesis.

Aims:

Our aim was to study the relationship between markers of cell proneness to apoptosis and indices of insulin resistance and dyslipidemia in children born with low birth weight (LBW).

Methods:

The study comprised 177 prepubertal children stratified by birth weight and their nutritional status into LBW (n = 138) and normal birth weight (NBW; n = 39) groups. We analyzed DNA from peripheral blood lymphocytes, separated by pulsed-field gel electrophoresis (PFGE), as well as the serum levels of cholesterol, HDL-cholesterol, triglycerides, fasting insulin and glucose, caspase 3, and BCL2.

Results:

LBW children with a BMI SDS >1.55 demonstrated increased content of the large fragments of the lymphocyte DNA [300-500 kb (DNA300-500 kb)] in electrophoretic slides (a marker of decreased chromatin stability and susceptibility of cells to apoptosis) compared to the NBW group. In these children the level of DNA300-500 kb exhibited a strong negative correlation with the serum level of antiapoptotic protein of BCL2 (r = -0.901). DNA300-500 kb significantly correlated with calculated indices of insulin resistance: HOMA-IR and QUICKI as well as with the indices of lipid homeostasis (Castelli and AIP).

Conclusions:

Increased susceptibility of lymphocytes to apoptosis correlated with a higher risk of insulin resistance and lipid disturbance in overweight or obese LBW children. A comprehensive study of the proneness of cells to apoptosis should be implemented to further investigate the pathomechanism of the metabolic syndrome in these children.

This study assessed whether exposure to pesticides elicits early biochemical changes in biomarkers of liver function and looked for potential gene-environmental interactions between pesticide exposure and polymorphisms of pesticide-metabolizing genes. A longitudinal study was conducted in farm-workers from Andalusia (South Spain), during two periods of the same crop season with different degree of pesticide exposure. Blood samples were taken for the measurement of serum and erythrocyte cholinesterase activities as well as for determining clinical chemistry parameters as biomarkers of liver function. Serum lipid levels were also measured as they may help to monitor the progress of toxic liver damage. A reduction in serum cholinesterase was associated with decreased levels of all clinical chemistry parameters studied except HDL-cholesterol. Conversely, a decreased erythrocyte cholinesterase (indicating long-term pesticide exposure) was associated with increased levels of aspartate aminotransferase and alkaline phosphatase and increased levels of triglycerides, total cholesterol and LDL-cholesterol, but reduced levels of HDL-cholesterol. Changes in liver biomarkers were particularly associated with the PON155M/192R haplotype. The obtained results therefore support the hypothesis that pesticide exposure results in subtle biochemical liver toxicity and highlight the role of genetic polymorphisms in pesticide-metabolizing enzymes as biomarkers of susceptibility for developing adverse health effects.

BACKGROUND:

Lipid synthesis and storage is accomplished by lipid droplets (LD). The perilipin family of LD-associated proteins, comprising 5 members (PLIN1-PLIN5), has been well characterized in adipocytes but not in sebocytes, epithelial cells in which LD formation is a key feature of the cellular differentiation.

METHODS:

Perilipins expression in the sebaceous gland cell line SZ95 and in human sebaceous glands was studied by qRT-PCR, Western blots, and immunohistochemistry. Lipid accumulation was evaluated by Nile red staining and mass spectrometry.

RESULTS:

PLIN2 and PLIN3 are the most abundant perilipins in undifferentiated sebocytes. Induction of lipogenesis by linoleic acid (LA) resulted in increased transcript levels of all perilipins except for PLIN3 and in a time-dependent increase of PLIN2 protein. Nile red staining revealed that siRNA-mediated downregulation of PLIN2 significantly impaired basal and LA-induced lipid accumulation. Mass spectrometry revealed PLIN2 deficiency to cause a reduction in the amount of several specific lipid fractions, including di- and triacyl-glycerol esters, phosphatidylcholine lipids, and ceramides in sebocytes under basal conditions. In contrast, PLIN2 downregulation exerted a statistically significant inhibitory effect only on the accumulation of specific LA-induced triglycerides. PLIN2-deficient mice showed normal morphology of sebaceous glands. However, their sebaceous glands were significantly reduced in size and showed less cell proliferation.

CONCLUSIONS:

PLIN2 is the major perilipin regulated during sebocyte differentiation in vitro. PLIN2 is also important for sebaceous lipid accumulation in vitro and regulates sebaceous gland size in vivo. GENERAL

SIGNIFICANCE:

Our study provides the first systematic analysis of LD-associated proteins in sebocytes.

Subclinical hypothyroidism (SCH) is defined by increased thyrotropin (TSH) and normal free thyroxine (fT4) levels. Controversial data are available regarding the effects of SCH on adipose tissue. Adiponectin and leptin are two major adipokines secreted from adipose tissue. We aimed to determine the levels of adiponectin and leptin in women with SCH and potential effects of L-thyroxine therapy on those levels. Forty three women with SCH and 53 age- and BMI-matched healthy euthyroid control women were included. Adiponectin and leptin levels, total cholesterol (TC), triglycerides (TG), HDL-, and LDL cholesterol, fat mass (FM) and fat-free mass (FFM) were determined in all participants. Patients received L-thyroxine treatment for 6 months after which all measurements were repeated. Patients with SCH and controls had similar baseline values for adiponectin, leptin, lipids, FM and FFM. All patients reached euthyroid status after 6 months of replacement therapy. Treatment resulted in an increase in adiponectin (p <0.01) and a decrease in leptin levels (p <0.05). Lipid levels, FM and FFM did not show a significant change. Achievement of euthyroid status by replacement therapy increases adiponectin and decreases leptin levels in women with SCH in this prospective study independent of a change in body fat mass.

The rise in childhood obesity has lead to an increased number of children with lipid abnormalities and the predominance of a combined dyslipidemic pattern characterized by a moderate-to-severe elevation in triglycerides, normal-to-mild mild elevation in LDL cholesterol and reduced HDL cholesterol. Although recently published National Heart, Lung and Blood Institute (NHLBI) guidelines represent a significant step forward in managing primary dyslipidemias in pediatric patients, there is still no general consensus regarding the pharmacologic treatment of obesity-related lipid abnormalities in children. The use of early pharmacologic intervention to control dyslipidemias and reduce cardiovascular risk in young children is only expected to increase given the steady increase in obesity and emergence of atherosclerotic disease in pre-adolescents. Despite the increasing use of lipid-lowering therapy in children over the last few years, diet and lifestyle modification remain the first line therapy. Given the challenges of instituting and maintaining lifestyle modification in pediatric patients, however, it is likely that institution of drug therapy may be required in many children. Of all the medications currently available, the fibric acid derivatives have a cholesterol lowering profile that is most likely to be effective in obese children with the high TG/low HDL phenotype and data from a recently published study of gemfibrozil in children with metabolic syndrome are promising. However, additional information regarding the short and long-term safety and efficacy of fibrate therapy in children with obesity-related lipid disorders is needed before use of these agents can be recommended.

An increased prevalence of female sexual dysfunction (FSD) has been reported in women with diabetes mellitus (DM). Our aim was to evaluate correlates (psychological, cardiovascular, and neurophysiologic) of FSD in DM women without chronic diabetic complications. Female Sexual Function Index (FSFI), Beck Depression Inventory (BDI), Michigan Diabetic Neuropathy Index (DNI), and the symptoms of diabetic neuropathy (SDN) questionnaires, metabolic variables, endothelial vascular function (flow-mediated dilation, FMD), echocardiography, and electromyography were studied. 109 pre-menopausal women (18-50 years) [48 with DM (14 type 1 DM, 34 type 2 DM, duration 12.6 ± 1.91 years), and 61 healthy women] received the above questionnaires; physical activity, smoking habits, parity, BMI, waist circumference, HOMA-IR index, fibrinogen, cholesterol (total, HDL, LDL), triglycerides, HbA1c, high-sensitivity C-reactive protein, total testosterone, and estradiol were measured; echocardiography, assessment of intima-media thickness (IMT), FMD, ECG (heart rate and Qtc, indexes of sympathetic activity), and electromyography were performed. FSFI total score and score for arousal, lubrication, and orgasm domains were lower in DM women than in controls (P < 0.05); DM women had higher BDI, Doppler A wave peak velocity, DNI, and SDN score (P < 0.001 to P < 0.04). Doppler E wave peak velocity, peroneal, posterior tibial and sural nerves conduction velocity and amplitude were lower in diabetic women than in controls (P < 0.05 to P < 0.001). FSFI score was positively correlated with physical activity, Doppler E wave peak velocity, and peroneal nerve amplitude and negatively with BDI, parity, IMT, SDN, and HbA1c (P < 0.05 to P < 0.001). At stepwise regression, SDN score (negatively) and Doppler E wave peak velocity (positively) predicted FSFI score (r = 507, P < 0.001). In conclusion, cardiovascular and neurological impairments are associated with FSD in diabetic women. Follow-up studies are required to evaluate sexual dysfunction as a risk factor for future cardiovascular or neurological events.

The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (Ndst1f/fAlbCre+ mice), decreased binding of ApoE-deficient TRLs to HSPGs on human hepatoma cells, and decreased clearance of ApoE-deficient [3H]TRLs in vivo. Evidence for a second ligand was suggested by the faster clearance of ApoE-deficient TRLs after injection into WT Ndst1f/fAlbCre- versus mutant Ndst1f/fAlbCre+ mice and elevated fasting and postprandial plasma triglycerides in compound Apoe-/-Ndst1f/fAlbCre+ mice compared with either single mutant. ApoAV emerged as a candidate based on 6-fold enrichment of ApoAV in TRLs accumulating in Ndst1f/fAlbCre+ mice, decreased binding of TRLs to proteoglycans after depletion of ApoAV or addition of anti-ApoAV mAb, and decreased heparan sulfate-dependent binding of ApoAV-deficient particles to hepatocytes. Importantly, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.

OBJECTIVE:

This study examined the influence of 3,4-benzopyrene (BaP), a compound found in cigarette smoke, on the formation of angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) formation in mice and the underlying mechanisms.

METHODS:

C57/B6n mice were divided into four groups. The control group received a weekly intraperitoneal injection of medium-chain triglycerides. The Ang II group received a daily Ang II infusion (0.72 mg/kg) and a weekly intraperitoneal injection of medium-chain triglycerides. The Ang II/BaP group received a daily Ang II infusion (0.72 mg/kg) and a weekly intraperitoneal BaP injection (10 mg/kg, dissolved in medium-chain triglycerides). The BaP group received a weekly intraperitoneal BaP injection (10 mg/kg). After 5 weeks, abdominal aortic diameter was determined. Aortic tissues underwent hematoxylin and eosin, Masson, and immunochemistry staining for evaluation of vascular wall structure, collagen, macrophage infiltration, matrix metalloproteinases (MMPs), and apoptosis.

RESULTS:

The Ang II infusion and BaP injection induced AAAs in 41.67% of mice vs 25% in the Ang II group (P < .05). The average aortic diameter increased in the Ang II/BaP group compared with the Ang II group (1.40 ± 0.25 vs 1.2 ± 0.23 mm; P < .05). Average aortic muscular cell apoptosis was higher in the Ang II/BaP group (31% ± 12%) than in the Ang II (19% ± 5%; P < .05) or BaP groups (23% ± 4%; P < .05). Aortic macrophage infiltration and expression of MMP-2, MMP-9, MMP-12, and nuclear factor-κB increased (0.56 ± 0.12, 0.47 ± 0.13, 0.49 ± 0.14, 0.49 ± 0.11, and 0.42 ± 0.12, respectively) in the Ang II/BaP group compared with the Ang II group (0.27 ± 0.08, 0.25 ± 0.06, 0.24 ± 0.09, 0.24 ± 0.09, and 0.23 ± 0.06, respectively; P < .05 for all).

CONCLUSIONS:

BaP promotes Ang II-induced AAA formation in mice via elevating infiltration of macrophages, activating nuclear factor-κB, upregulating the expression of MMP-2, MMP-9, and MMP-12, and increasing the apoptosis of vascular muscle cells in its synergistic effect with Ang II in aortic wall.

- Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP1.- It has recently been discovered that BAT is present and active in adults. BAT is situated predominantly around the aorta and in the supraclavicular area.- BAT volume and activity are lower in individuals who are obese. This suggests that BAT significantly contributes to total energy expenditure. .- Several pathological conditions that are accompanied by activation of BAT, such as hyperthyroidism and phaeochromocytoma, result in the increased expenditure of energy and in weight loss.- Various ways in which BAT can be manipulated to increase the expenditure of energy have been identified, e.g. exposure to cold, the use of so-called uncoupling agents or the administration of the hormone irisin.- The activation of BAT could potentially be used to induce weight loss.