Lipid Changes Research Articles

Acute and sub-acute toxicological evaluation of <em>Barleria prionitis</em> Linn. in Wistar albino rats

Despite the wide usage of Barleria prionitis Linn. (Acanthaceae) in traditional medicine, controversial findings have been reported on possible toxic effects of the plant. The present study evaluated the acute and sub-acute toxic/adverse effects of B. prionitis using a healthy Wistar albino rat model. Repeated oral administration of the hexane, ethyl acetate, butanol, and aqueous extracts of the whole plant at therapeutic doses (25, 80, 70, and 120 mg/kg) revealed no mortality or treatmentrelated hematological and biochemical changes in experimental rats. However, statistically significant changes were observed in a few red cell and white cell parameters, suggesting increased erythropoiesis and immunity in experimental rats treated with B. prionitis (p<0.05). The findings on total cholesterol, glucose, and liver function tests revealed potential changes in lipid and carbohydrate metabolism and liver functions after treatments. However, the absence of statistically significant changes in the plant treated groups was noted compared to their respective vehicle control groups (p>0.05), and the lack of those changes in male and female rats excludes potential toxic effects from B. prionitis extracts. The findings on the relative weight of organs and histopathology further corroborated the safe use of the selected extracts at doses in therapeutic applications. In conclusion, the findings on acute and 28-day repeated dose oral toxicity assessments of the whole plant extracts resulted in neither mortality nor treatment-related hematological, biochemical, and histopathological changes in healthy Wistar albino rats.

Lipid dynamics of 'Fenjiao' bananas (Musa ABB Pisang Awak) during post-ripening based on lipidomics analysis

Changes in cellular lipid homeostasis during ripening of ‘Fenjiao’ bananas (Musa ABB Pisang Awak) significantly affected its storage tolerance, and an in-depth understanding of the changes in cellular lipids during fruit ripening could provide more information and basic data for post-harvest quality regulation of 'Fenjiao' bananas. In this study, a comprehensive metabolomics approach was employed to annotate and characterize a total of 184 lipids, which encompassed glycerides, glycero-phospholipids, sphingolipids, and sterols. In the pulp of 'Fenjiao' bananas at three different stages of ripening (color-transferring, yellow-ripening, and over-ripening), of which glycerides and glycerophospho-lipids were the most predominant lipid constituents in the pulp of ‘Fenjiao’ bananas, with the percentages of the species accounting for 60.33% and 30.43%, respectively. During the post-ripening process of ‘Fenjiao’ bananas, the percentage of glycerides in the pulp exhibited a decreasing trend followed by an increasing trend. In contrast, the trend of glycerophospholipids was opposite to that of glycerides, showing an increasing trend followed by a decreasing trend. The tria-cylglycerol (TAG) content will increase significantly during the senescence stage of the 'Fenjiao' bananas, whereas the levels of diglycerides (DAG), Phosphatidylinositol (PI), Pho-sphatidylcholine (PC), and Phosphatidylethanolamine (PE) will gradually decrease. Through analysis of the differential lipid metabolites, it was discovered that these lipids were primarily enriched in the glycerolipid metabolism, glycerophospholipid metabolism, biosynthesis of unsaturated fatty acids, saturated fatty acid biosynthesis, and phosphatidylinositol signaling pathway. This study is the first to describe and analyze the lipid dynamics during the post-ripening process of 'Fenjiao' bananas, providing valuable insights into its cellular lipid metabolism during this stage.

Development of an Efficient On-Tissue Epoxidation Reaction Mediated by Urea Hydrogen Peroxide for MALDI MS/MS Imaging of Lipid C═C Location Isomers.

Unsaturated lipids containing different numbers and locations of C═C bonds are significantly associated with a variety of cellular and metabolic functions. Although matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) has been used to visualize the spatial distribution patterns of various lipids in biological tissues, in situ identification, discrimination, and visualization of lipid C═C location isomers remain challenging. Herein, an efficient and fast on-tissue chemical derivatization (OTCD) approach was developed to pinpoint the locations of C═C bonds in complex lipids in situ via methyltrioxorhenium (MTO)-catalyzed epoxidation of C═C with a urea hydrogen peroxide (UHP)/hexafluoroisopropanol (HFIP) system. The efficiency of OTCD could reach 100% via one-step spray deposition of the solution mixture of MTO/UHP/HFIP at room temperature. The developed OTCD method provided rich structural information on lipid C═C location isomers, and their accurate spatial distribution patterns were resolved in mouse brain tissues. Tissue-specific distributions and changes of lipid C═C location isomers in the liver sections of obese ob/ob and diabetic db/db mice were further investigated, and their correlation in two animal models was revealed. The simplicity and high efficiency of the OTCD method developed for MALDI tandem MSI of lipid C═C location isomers possess great potential for functional spatial lipidomics.

Changes in liver metabolic pathways demonstrate efficacy of the combined dietary and microbial therapeutic intervention in MASLD mouse model

ObjectiveMetabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease globally, yet no therapies are approved. The effects of Escherichia coli Nissle 1917 expressing aldafermin, an engineered analog of the intestinal hormone FGF19, in combination with dietary change were investigated as a potential treatment for MASLD. MethodsMASLD was induced in C57BL/6J male mice by American lifestyle-induced obesity syndrome diet and then switched to a standard chow diet for seven weeks. In addition to the dietary change, the intervention group received genetically engineered E. coli Nissle expressing aldafermin, while control groups received either E. coli Nissle vehicle or no treatment. MASLD-related plasma biomarkers were measured using an automated clinical chemistry analyzer. The liver steatosis was assessed by histology and bioimaging analysis using Fiji (ImageJ) software. The effects of the intervention in the liver were also evaluated by RNA sequencing and liquid-chromatography-based non-targeted metabolomics analysis. Pathway enrichment studies were conducted by integrating the differentially expressed genes from the transcriptomics findings with the metabolites from the metabolomics results using Ingenuity pathway analysis. ResultsAfter the intervention, E. coli Nissle expressing aldafermin along with dietary changes reduced body weight, liver steatosis, plasma aspartate aminotransferase, and plasma cholesterol levels compared to the two control groups. The integration of transcriptomics with non-targeted metabolomics analysis revealed the downregulation of amino acid metabolism and related receptor signaling pathways potentially implicated in the reduction of hepatic steatosis and insulin resistance. Moreover, the downregulation of pathways linked to lipid metabolism and changes in amino acid-related pathways suggested an overall reduction of oxidative stress in the liver. ConclusionsThese data support the potential for using engineered microbial therapeutics in combination with dietary changes for managing MASLD.

Lipidomics reveals lipid changes in the intramuscular fat of geese at different growth stages

The quality (color, tenderness, juiciness, protein content, and fat content) of poultry meat is closely linked to age, with older birds typically exhibiting increased intramuscular fat (IMF) deposition. However, specific lipid metabolic pathways involved in IMF deposition remain unknown. To elucidate the mechanisms underlying lipid changes, we conducted a study using meat geese at 2 distinct growth stages (70 and 300 d). Our findings regarding the approximate composition of the meat revealed that as the geese aged 300 d, their meat acquired a chewier texture and displayed higher levels of IMF. Liquid chromatography-mass spectrometry (LC-MS) was employed for lipid profiling of the IMF. Using a lipid database, we identified 849 lipids in the pectoralis muscle of geese. Principal component analysis and orthogonal partial least squares discriminant analysis were used to distinguish between the 2 age groups and identify differential lipid metabolites. As expected, we observed significant changes in 107 lipids, including triglycerides, diglycerides, phosphatidylethanolamine, alkyl-glycerophosphoethanolamine, alkenyl-glycerophosphoethanolamine, phosphatidylcholine, phosphatidylinositol, lysophosphatidylserine, ceramide-AP, ceramide-AS, free fatty acids, cholesterol lipids, and N-acyl-lysophosphatidylethanolamine. Among these, the glyceride molecules exhibited the most pronounced changes and played a pivotal role in IMF deposition. Additionally, increased concentration of phospholipid molecules was observed in breast muscle at 70 d. Unsaturated fatty acids attached to lipid side chain sites enrich the nutritional value of goose meat. Notably, C16:0 and C18:0 were particularly abundant in the 70-day-old goose meat. Pathway analysis demonstrated that glycerophospholipid and glyceride metabolism were the pathways most significantly associated with lipid changes during goose growth, underscoring their crucial role in lipid metabolism in goose meat. In conclusion, this work provides an up-to-date study on the lipid composition and metabolic pathways of goose meat and may provide a theoretical basis for elucidating the nutritional value of goose meat at different growth stages.

Revealing Further Insights into Astringent Seeds of Chinese Fir by Integrated Metabolomic and Lipidomic Analyses.

Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.) stands as one of the pivotal afforestation tree species and timber resources in southern China. Nevertheless, the occurrence of seed abortion and a notably high proportion of astringent seeds significantly curtail the yield and quality of elite seeds, resulting in substantial economic losses. The development of astringent seeds is accompanied by significant physiological and biochemical alterations. Here, the first combined lipidomic and metabolomic analysis was performed to gain a comprehensive understanding of astringent seed traits. A total of 744 metabolites and 616 lipids were detected, of which 489 differential metabolites and 101 differential lipids were identified. In astringent seeds, most flavonoids and tannins, as well as proline and γ-aminobutyric acid, were more accumulated, along with a notable decrease in lipid unsaturation, indicating oxidative stress in the cells of astringent seeds. Conversely, numerous elemental metabolites were less accumulated, including amino acids and their derivatives, saccharides and alcohols, organic acids and nucleotides and their derivatives. Meanwhile, most lipid subclasses, mainly associated with energy storage (triglyceride and diglyceride) and cell membrane composition (phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine), also exhibited significant reductions. These results reflected a disruption in the cellular system or the occurrence of cell death, causing a reduction in viable cells within astringent seeds. Furthermore, only one lipid subclass, sphingosine phosphate (SoP), was more accumulated in astringent seeds. Additionally, lower accumulation of indole-3-acetic acid and more accumulation of salicylic acid (SA) were also identified in astringent seeds. Both SA and SoP were closely associated with the promotion of programmed cell death in astringent seeds. Collectively, our study revealed significant abnormal changes in phytohormones, lipids and various metabolites in astringent seeds, allowing us to propose a model for the development of astringent seeds in Chinese fir based on existing research and our findings. This work enriches our comprehension of astringent seeds and presents valuable bioindicators for the identification of astringent seeds.

Paradoxical Effects of Prolonged Insufficient Sleep on Lipid Profile: A Pooled Analysis of 2 Randomized Trials.

Background Insufficient sleep is associated with increased cardiovascular disease risk, but causality is unclear. We investigated the impact of prolonged mild sleep restriction (SR) on lipid and inflammatory profiles. Methods and Results Seventy-eight participants (56 women [12 postmenopausal]; age, 34.3±12.5 years; body mass index, 25.8±3.5 kg/m2) with habitual sleep duration 7 to 9 h/night (adequate sleep [AS]) underwent two 6-week conditions in a randomized crossover design: AS versus SR (AS-1.5 h/night). Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, and inflammatory markers (CRP [C-reactive protein], interleukin 6, and tumor necrosis factor-α) were assessed. Linear models tested effects of SR on outcomes in the full sample and by sex+menopausal status (premenopausal versus postmenopausal women+men). In the full sample, SR increased high-density lipoprotein cholesterol compared with AS (β=1.2±0.5 mg/dL; P=0.03). Sex+menopausal status influenced the effects of SR on change in total cholesterol (P-interaction=0.04), LDL-C (P-interaction=0.03), and interleukin 6 (P-interaction=0.07). Total cholesterol and LDL-C decreased in SR versus AS in premenopausal women (total cholesterol: β=-4.2±1.9 mg/dL; P=0.03; LDL-C: β=-6.3±2.0 mg/dL; P=0.002). Given paradoxical effects of SR on cholesterol concentrations, we explored associations between changes in inflammation and end point lipids under each condition. Increases in interleukin 6 and tumor necrosis factor-α during SR tended to relate to lower LDL-C in premenopausal women (interleukin 6: β=-5.3±2.6 mg/dL; P=0.051; tumor necrosis factor-α: β=-32.8±14.2 mg/dL; P=0.027). Conclusions Among healthy adults, prolonged insufficient sleep does not increase atherogenic lipids. However, increased inflammation in SR tends to predict lower LDL-C in premenopausal women, resembling the "lipid paradox" in which low cholesterol associates with increased cardiovascular disease risk in proinflammatory conditions. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02835261, NCT02960776.

Seasonal effect on fatty acid composition in phospholipid classes and triacylglycerols of male Capoeta umbla

The seasonal changes in muscle tissue, total lipids and fatty acid composition of phospholipids (PL), triacylglycerol (TAG), and phospholipid classes of male Capoeta umbla were investigated in this study. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS) were identified as the major phospholipids (PLs) in the muscle tissue (PS). Triacylglycerols showed high contents of MUFA, 14:0, 16:1n-7, 18:1n-9, 18:2n-6, and 18:3n-3; while phospholipids presented high contents of AA, DHA, and 18:0. Myristic acid, 16:1n-7, 18:1n-9, monounsaturated fatty acids (MUFA), linoleic acid (18:2n-6), and linolenic acid (18:3n-3) were shown to be present in larger concentrations in TAG than in PL classes. In PL classes, 16:0, 18:0, arachidonic acid (20:4n-6) (AA), eicosapentaenoic acid (EPA) (20:5n-3), docosahexaenoic acid (DHA) (22:6n-3) and polyunsaturated fatty acid (ΣPUFA) were higher than the TAG fraction. The fatty acid composition of total lipid and lipid classes (TAG and PL) were affected by the seasonal variations and lipid fraction.

What are the most effective biotic and abiotic factors affecting fatty acid composition of Garra rufa (Heckel, 1843)?

Specimens of Garra rufa were collected from a warm river and a cool stream in the Bingöl Province, Turkey, once a month over a period of one year. The effects of month, season, gender and location on the fatty acid composition in the muscle and the lipid content were investigated and dietary marker fatty acids were used to obtain dietary preferences in different locations (Ilıcalar, Garip) and periods. Total lipid change was seasonally significant (ANOSIM-R=0.49) at both locations and 18:1ω9, 20:5ω3 and 20:6ω3 were the most abundant dietary fatty acids. Although G. rufa are predominantly herbivores, they can also feed omnivorously on mixed diets depending on the presence and absence of their primary diet. The effect of season was significant on fatty acid composition, regardless of the location (Pperm=0.001). Significant seasonal changes in all the fatty acid compositions could be attributed to seasonal changes in the abundance and diversity of dietary sources in the environment due to the effect of temperature.

Early-stage mapping of macromolecular content in APPNL-F mouse model of Alzheimer's disease using nuclear Overhauser effect MRI.

Non-invasive methods of detecting early-stage Alzheimer's disease (AD) can provide valuable insight into disease pathology, improving the diagnosis and treatment of AD. Nuclear Overhauser enhancement (NOE) MRI is a technique that provides image contrast sensitive to lipid and protein content in the brain. These macromolecules have been shown to be altered in Alzheimer's pathology, with early disruptions in cell membrane integrity and signaling pathways leading to the buildup of amyloid-beta plaques and neurofibrillary tangles. We used template-based analyzes of NOE MRI data and the characteristic Z-spectrum, with parameters optimized for increase specificity to NOE, to detect changes in lipids and proteins in an AD mouse model that recapitulates features of human AD. We find changes in NOE contrast in the hippocampus, hypothalamus, entorhinal cortex, and fimbria, with these changes likely attributed to disruptions in the phospholipid bilayer of cell membranes in both gray and white matter regions. This study suggests that NOE MRI may be a useful tool for monitoring early-stage changes in lipid-mediated metabolism in AD and other disorders with high spatial resolution.

Changes in Lipids in Granulomatosis with Polyangiitis Relates to Glucocorticoids and History of Hypertension.

Granulomatosis with polyangiitis (GPA) is an ANCA-associated small-vessel vasculitis. Vessel wall inflammation induces multiple vascular damages, leading to accelerated atherosclerosis. Metabolic profile and cardiovascular risk are somewhat understood in GPA patients. Cardiovascular atherosclerotic disease (ASCVD) may represent a risk for outcomes. Our purpose is to evaluate ASCVD risk in GPA patients. Thirty-six patients received GPA diagnosis (T0) and were evaluated after 1 (T1) and 2 (T2) years follow-up. All patients were treated with high-dose glucocorticoid, one-year tapered, along with immunosuppressants. Total cholesterol significantly increased in T1 vs. T0 and T2. LDL exhibited the same trend, while triglycerides increased in both T1 and T2 vs. T0. No difference was found in HDL. A significant hsCRP decrease was detected at T1 and T2 vs. T0, but not between T2 and T1. Moreover, we found a significant reduction in ESR at T2 compared with T1 and T0 and at T1 compared to T0. Hypertensive patients presented a pronounced increase in lipids, while inflammation reduced slowly compared to normotensives. Our data suggest that the increase in cholesterol and LDL in T1 is a consequence of glucocorticoids. These data can be useful in the evaluation of both CV diseases and lipid metabolism, which are closely related to vessel inflammation.

Maternal low-protein diet alters hepatic lipid accumulation and gene expression related to glucose metabolism in young adult mouse offspring fed a postweaning high-fat diet

Maternal consumption of low-protein (LP) diet during pregnancy has been demonstrated to increase the chances of adult offspring developing metabolic syndrome, and this risk can be exacerbated when the postnatal diets do not align with the prenatal conditions. However, in our previous study, focusing on serum parameters and gene expression patterns within adipose tissue, we discovered the presence of “healthy obesity” in young adult offspring from dams that were fed an LP, as a response to a postweaning high-fat (HF) diet. Here, we subsequently investigated the role played by the liver and skeletal muscle in alleviation of insulin resistance in male offspring that were fed either control (C/C group) or HF diet (C/HF and LP/HF groups) for 22 weeks. While a postweaning HF diet increased liver weight and hepatic triglyceride (TG) and cholesterol levels in offspring of control dams, these levels were lower in the LP/HF group compared to the C/HF group. Analysis of the liver transcriptome identified 430 differentially expressed genes (DEGs) in the LP/HF and C/HF comparison. Especially, downregulated DEGs were enriched in carbohydrate metabolism and the levels of DEGs were significantly correlated with the levels of markers for serum glucose homeostasis and hepatic lipid accumulation. In the LP/HF group compared to the C/HF group, there was a decrease in the gastrocnemius muscle weight, while no differences were observed in gene expression levels associated with muscle fiber phenotype, mitochondrial function, and inflammation. In conclusion, maternal LP diet induced changes in lipid and glucose metabolism within the liver, similar to what was observed in adipose tissue, while there were no alterations in metabolic functions in the skeletal muscle in young offspring mice fed an HF diet. Further research that investigating the enduring impact of nutritional transition on offspring is essential to gain a comprehensive grasp of developmental programming throughout their entire lifespan.

Perilipin 2-positive mononuclear phagocytes accumulate in the diabetic retina and promote PPARγ-dependent vasodegeneration.

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR.

Alzheimer's Disease in Diabetic Patients: A Lipidomic Prospect.

Diabetes Mellitus (DM) and Alzheimer's disease (AD) have been two of the most common chronic diseases affecting people worldwide. Type 2 DM (T2DM) is a metabolic disease depicted by insulin resistance, dyslipidemia, and chronic hyperglycemia while AD is a neurodegenerative disease marked by Amyloid β (Aβ) accumulation, neurofibrillary tangles aggregation, and tau phosphorylation. Various clinical, epidemiological, and lipidomics studies have linked those diseases claiming shared pathological pathways raising the assumption that diabetic patients are at an increased risk of developing AD later in their lives. Insulin resistance is the tipping point beyond where advanced glycation end (AGE) products and free radicals are produced leading to oxidative stress and lipid peroxidation. Additionally, different types of lipids are playing a crucial role in the development and the relationship between those diseases. Lipidomics, an analysis of lipid structure, formation, and interactions, evidently exhibits these lipid changes and their direct and indirect effect on Aβ synthesis, insulin resistance, oxidative stress, and neuroinflammation. In this review, we have discussed the pathophysiology of T2DM and AD, the interconnecting pathological pathways they share, and the lipidomics where different lipids such as cholesterol, phospholipids, sphingolipids, and sulfolipids contribute to the underlying features of both diseases. Understanding their role can be beneficial for diagnostic purposes or introducing new drugs to counter AD.

Comparative lipidomics analysis of in vitro lipid digestion of sheep milk: Influence of homogenization and heat treatment

This study investigated the changes in sheep milk lipids during in vitro gastrointestinal digestion in response to heat treatment (75°C/15 s and 95°C/5 min) and homogenization (200/50 bar) using lipidomics. Homogenized and pasteurized sheep milk had higher levels of polar lipids in gastric digesta emptied at 20 min than raw sheep milk. Intense heat treatment of homogenized sheep milk resulted in a reduced level of polar lipids compared with homogenized-pasteurized sheep milk. The release rate of free fatty acids during small intestinal digestion for gastric digesta emptied at 20 min followed the order: raw ≤ pasteurized < homogenized-pasteurized ≤ homogenized-heated sheep milk; the rate for gastric digesta emptied at 180 min showed a reverse order. No differences in the lipolysis degree were observed among differently processed sheep milks. These results indicated that processing treatments affect the lipid composition of digesta and the lipolysis rate but not the lipolysis degree during small intestinal digestion.

Quantitative biochemical phenotypic heterogeneity of senescent macrophage at a single cell level by Synchrotron Radiation Fourier Transform Infrared Microspectroscopy

Macrophage senescence plays an important role in pathophysiological process of age-related diseases such as atherosclerosis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer. After macrophage senescence, the biochemical phenotypes related to biological functions showed great heterogeneity. However, the biochemical phenotype and phenotypic heterogeneity of senescent macrophage has not been fully understood. Exploring the phenotype of biochemical substances in senescent macrophage will be helpful for understanding the function of senescent macrophage and finding out the potential mechanism between immune macrophage senescence and age-related diseases. In this study, we employed SR-FTIR microspectroscopy to detect the biochemical phenotype and phenotypic heterogeneity of single macrophage. The whole infrared spectra of senescent macrophages shifted, indicating biochemical substance changes within senescent macrophages. PCA and intercellular Euclidean distance statistical analysis based on specific spectra regions revealed dynamic changes of lipids and proteins during macrophage senescence. This proved that SR-FTIR microspectroscopy is an effective tool to detect the single cell biochemical phenotype transformation and phenotypic heterogeneity during macrophage senescence. It is of great significance to provide an evaluation method or clue for the study of cellular functions related to intracellular biochemical substances.Graphical abstract

Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model

Expansion of a triplet repeat tract in exon 1 of the HTT gene causes Huntington’s disease (HD). The mutant HTT protein (mHTT) has numerous aberrant interactions with diverse, pleiomorphic effects. Lowering mHTT is a promising approach to treat HD, but it is unclear when lowering should be initiated, how much is necessary, and what duration should occur to achieve benefits. Furthermore, the effects of mHTT lowering on brain lipids have not been assessed. Using a mHtt-inducible mouse model, we analyzed mHtt lowering initiated at different ages and sustained for different time-periods. mHTT protein in cytoplasmic and synaptic compartments of the striatum was reduced 38-52%; however, there was minimal lowering of mHTT in nuclear and perinuclear regions where aggregates formed at 12 months of age. Total striatal lipids were reduced in 9-month-old LacQ140 mice and preserved by mHtt lowering. Subclasses important for white matter structure and function including ceramide (Cer), sphingomyelin (SM), and monogalactosyldiacylglycerol (MGDG), contributed to the reduction in total lipids. Phosphatidylinositol (PI), phosphatidylserine (PS), and bismethyl phosphatidic acid (BisMePA) were also changed in LacQ140 mice. Levels of all subclasses except ceramide were preserved by mHtt lowering. mRNA expression profiling indicated that a transcriptional mechanism contributes to changes in myelin lipids, and some but not all changes can be prevented by mHtt lowering. Our findings suggest that early and sustained reduction in mHtt can prevent changes in levels of select striatal proteins and most lipids, but a misfolded, degradation-resistant form of mHTT hampers some benefits in the long term.

A-205 Optimized Time Interval for the Measurement of Plasma Lipids for Assessing Cardiovascular Disease Risk

Abstract Background The measurement of plasma lipids are used to predict atherosclerotic cardiovascular disease (ASCVD) risk and for the management of lipid-lowering therapy. The general recommendation is that plasma lipids should be measured at least every 5 years, but the ideal time may vary depending on the baseline risk, which we examined in this study. Methods Using lipid values and other risk factors from the National Health and Nutrition Examination Survey (NHANES) (no diabetes, no lipid medications, n = 9704), which is designed to be representative of the US-general population, we calculated a baseline 10-year ASCVD risk with the pooled cohort risk equations (PCE). Future 10-year risk scores were estimated by chronologically increasing age of the subjects and projecting future systolic blood pressure (SBP) and lipid changes, using the mean-percentile age group change in the NHANES population for SBP (no hypertension medications, n = 17 329) and the Lifelines Cohort study for lipids (no CVD or lipid medications, n = 133 540). Crossing high-risk (&amp;gt;20%/10-years; 25% decison limit) and intermediate risk (&amp;gt;7.5%/10-years; 50% decision limit) PCE thresholds were calculated by baseline age to determine the best time intervals for testing lipids. Results As shown in the figure, the likelihood of crossing the intermediate or high-risk threshold depends on the baseline risk. Individuals that are close to one of the risk thresholds are more likely to cross it in the subsequent years. Based on this analysis, we recommend the following time intervals for lipid testing: Baseline risk &amp;lt; 5%/10-year: 5-years, baseline risk 5–15%/10-year: 3-years, baseline risk 16–20%/10-year: 1–2 years. Conclusions More frequent lipid testing than once every 5 years is desirable, because it would identify at risk patients sooner and allow for earlier therapeutic intervention, which has been shown to increase the effectiveness of statin therapy for reducing ASCVD events.

Effect of Coccinia grandis (Linn.) Voigt extract on glucose metabolism markers in a prediabetic population: A double-blind randomised clinical trial

BackgroundThere is increasing interest in the use of herbal medicines to prevent and manage the symptoms of type 2 diabetes mellitus (T2DM). Coccinia grandis has been traditionally used for blood glucose regulation and has shown promise in clinical trials for T2DM although it has not yet been assessed as an anti-glycaemic agent in a prediabetic population. ObjectiveThis study aimed to assess the safety as well as the efficacy of a C. grandis extract in reducing blood glucose levels in a non-medicated prediabetic cohort over 12 weeks. MethodsThe study was a single-site, double-blind, placebo-controlled randomised clinical trial conducted in 48 medically diagnosed prediabetic adults aged 27 to 73 years. Participants received either 1000 mg of a dried C. grandis hydroalcoholic extract per day (equivalent to 15 g/day of dried herb) or placebo (control) for 12 weeks. The primary outcome measure was group change scores in fasting blood glucose (FBG) levels measured at baseline, week 6 and week 12. Secondary outcome measures were 2 h post-prandial blood glucose (PPBG), fasting and 2 h post-prandial insulin (FI and PPI), glycated haemoglobin (HbA1c), c-peptide, full blood count (FBC), lipids (triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), emotional states of depression, anxiety and stress (DASS-21), adverse reactions and tolerability. ResultsAt 12 weeks there was a significant difference between the C. grandis and control groups in the change between their pre and post treatment measurements of FBG (p = 0.019, CI -1.272 to -0.105), 2 h PPBG (p = 0.039, CI 0.212 to 1.392) and TG (p= 0.046). Additionally, although non-significant, the difference between the change in PPI levels (p = 0.061) is worthy of further exploration to provide an understanding of the mechanisms of action of C. grandis extract in managing glucose dysregulation. There were no changes in HbA1c, lipids or biochemical markers in either group after treatment. The C. grandis extract was well tolerated and no adverse events were reported over the 12 weeks. ConclusionC. grandis may be a suitable candidate for managing blood glucose dysregulation in those with prediabetes and further studies are warranted.

Lipid peroxidation and changes in major antioxidant markers in copper quinolate fungicide-exposed rats.

The present study investigated the toxic effects of sub-chronic exposure to copper quinolate (CuQ) fungicide on liver and kidney function. Twenty-four adult male Wistar rats were equally divided into a control group, and three treated groups received, respectively, by oral gavage, three increasing doses of CuQ: 47; 67.1; and 94mg/kg b.w corresponding, respectively, LD50/100, LD50/70, and LD50/50 daily for 8weeks. CuQ resulted in a significant increase in the serum enzymatic activity of aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and the serum levels of urea, creatinine, uric acid, and malondialdehyde, along with a marked decrease in alanine aminotransferase (ALT) activity, and the contents of total protein and albumin compared to those of the control group. Furthermore, glutathione content and the enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx) decreased significantly in a dose-dependent manner with respect to CuQ. The adverse effects of CuO were supported by the histopathological evaluations of liver and kidney tissues. Conclusively, sub-chronic CuQ exposure was shown to induce kidney and liver oxidative damage and dysfunction.