Lipid Modulation Research Articles

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.

Docosahexaenoic acid and phenazine ethosulfate are not efficient lipid modulators for porcine in vitro maturation systems.

The high lipid content in porcine oocytes impairs in vitro embryo production (IVP). Here, we evaluated the influence of two different lipid modulators during in vitro maturation (IVM) on the embryo development and the lipid content of oocytes and embryos. In Experiment I, oocytes were exposed to 50μM docosahexaenoic acid (DHA) with (+) or without (-) the presence of porcine follicular fluid (pFF). In Experiment II, phenazine ethosulfate (PES) was added during IVM at two concentrations (0.5 and 0.05μM). The pFF- with 50μM DHA treatment impaired nuclear maturation, cleavage and blastocyst rates (p < 0.05). Oocytes in pFF- media accumulated less lipids (p < 0.05). The addition of 0.5μM PES reduced all development rates (p < 0.05) and resulted in higher lipid content for oocytes and embryos. Only 0.05μM PES oocytes matured similarly to the control (p > 0.05), although embryo development and embryo lipid content was similar to 0.5μM PES oocytes (p > 0.05). Thus, 50μM DHA supplementation in the IVM medium without pFF impaired oocyte maturation and embryo development rates without interfering in oocyte lipid content even in the presence of pFF. Maturation with PES neither favored porcine embryo development nor reduced their lipid content.

Exploring Pleiotropic Effects of Lipid Modifiers and Targets on Measures of the Coagulation System with Genetics.

Statins have long been suspected to have pleiotropic effects via thrombotic factors. Randomized controlled trials are too limited to be definitive. We examined the associations of genetically mimicking effects of statins, PCSK9 inhibitors, and alternative lipid targets (in genes LDLR, APOC3, and LPL) on key indicators of coagulation system function, i.e., prothrombin time (PT) and activated partial thromboplastin time (aPTT). We assessed the effect of established genetic mimics of effects of lipid modifiers and alternative lipid treatment targets on PT (n = 58,110) and aPTT (n = 37,767), all transformed to z-scores, using Mendelian randomization taking advantage of Biobank Japan. Ischemic heart disease (IHD) was a control outcome. Genetically mimicked effects of statins increased PT by 0.31 standard deviation (SD) per SD increase in low-density lipoprotein (95% confidence interval [CI]: 0.10-0.51) based on rs12916 but did not affect aPTT. Genetically mimicking effects of targeting LDLR increased PT based on rs688 (0.33 SD per SD increase in triglyceride, 95% CI: 0.03-0.63) but did not affect aPTT. Genetically mimicking effects of PCSK9 inhibitors or targeting APOC3 or LPL had no effect on PT or aPTT. Genetically mimicking effects of statins, PCSK9 inhibitors, and alternative lipid targets reduced risk of IHD in Biobank Japan. Statins, and possibly targeting LDLR, may also act via a coagulation cascade factor, likely specific to the extrinsic or common pathway. Further elucidation of the mechanistic pathway may facilitate development of new interventions and inform use of statins particularly in relation to use of other anticoagulants.

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches.

The multiple roles of lipid metabolism in yeast physiology during beer fermentation.

The ability of brewing yeasts (Saccharomyces cerevisiae and Saccharomyces pastorianus) to cope with the toxic effects of ethanol during beer fermentation depends on the modulation of lipid and lipid droplets (LDs) biosynthesis, which affects membrane fluidity. However, it has been demonstrated that lipids and LDs can modulate different biological mechanisms associated to ethanol tolerance, including proteostasis and autophagy, leading to the hypothesis that lipid and LDs biosynthesis are integrative processes necessary for ethanol tolerance in yeast. Supporting this hypothesis, a transcriptome and systems biology analyses indicated the upregulation of autophagy, lipid biosynthesis, and proteostasis (ALP)-associated genes in lager yeast during beer fermentation, whose respective proteins interact in a shortest-pathway ALP network. These results indicated a cross-communication between various pathways linked to inter-organelle autophagy, lipid metabolism, and proteostasis (ALP) during lager beer fermentation, thus highlighting the importance of lipids for beer fermentation.

Drug targeting opportunities en route to Ras nanoclusters.

Disruption of the native membrane organization of Ras by the farnesyltransferase inhibitor tipifarnib in the late 1990s constituted the first indirect approach to drug target Ras. Since then, our understanding of how dynamically Ras shuttles between subcellular locations has changed significantly. Ras proteins have to arrive at the plasma membrane for efficient MAPK-signal propagation. On the plasma membrane Ras proteins are organized into isoform specific proteo-lipid assemblies called nanocluster. Recent evidence suggests that Ras nanocluster have a specific lipid composition, which supports the recruitment of effectors such as Raf. Conversely, effectors possess lipid-recognition motifs, which appear to serve as co-incidence detectors for the lipid domain of a given Ras isoform. Evidence suggests that dimeric Raf proteins then co-assemble dimeric Ras in an immobile complex, thus forming the minimal unit of an active nanocluster. Here we review established and novel trafficking chaperones and trafficking factors of Ras, along with the set of lipid and protein modulators of Ras nanoclustering. We highlight drug targeting approaches and opportunities against these determinants of functional Ras membrane organization. Finally, we reflect on implications for Ras signaling in polarized cells, such as epithelia, which are a common origin of tumorigenesis.

The use of anti-hyperlipidemia in a private hospital in Yogyakarta during 2013-2019

Background: Lipid modifying agents have an important role in the primary and secondary prevention of cardiovascular diseases such as coronary heart disease and stroke. The use of lipid-modifying agents tends to increase along with the increasing prevalence of these diseases. Objectives: To determine the utilization of lipid modifying agents for hospitalized patients in a private hospital in Yogyakarta during the period of 2013 - 2019 in regard to the agents used and their quantity. Methods: The main data for this study were aggregate data on the use of lipid modifying agents for hospitalized patients during 2013-2019 obtained from the hospital pharmacy department. After identification of the names of lipid modifying agents, the quantities of these drugs were then calculated in units of defined daily dose (DDD) and the final quantity was expressed in DDD/100 bed days (BD). The R2 value from linear regression was used to determine the trend of use of individual agents over the period. Results: There were two pharmacological subgroups of lipid modifying agents used during the period of 2013 – 2019 with an average of total quantity of 14.81 DDD/100 BD. Utilization of statins was approximately 90% of the total use, and utilization of fibrates tended to decrease over the period. Individually, simvastatin use decreased significantly over the period (R2 = 0.885), but atorvastatin use continued to increase (R2 = 0.908) with 10-fold increase from 2013 to 2019. Conclusion: The lipid modifying agents used during the period 2013 - 2019 were predominantly statins, and the utilization of atorvastatin increased significantly during this period. Keywords: lipid modifying agents, ATC/DDD, fibrates, statins

Links between ceramides and cardiac function.

Total ceramide levels in cardiac tissue relate to cardiac dysfunction in animal models. However, emerging evidence suggests that the fatty acyl chain length of ceramides also impacts their relationship to cardiac function. This review explores evidence regarding the relationship between ceramides and left ventricular dysfunction and heart failure. It further explores possible mechanisms underlying these relationships. In large, community-based cohorts, a higher ratio of specific plasma ceramides, C16 : 0/C24 : 0, related to worse left ventricular dysfunction. Increased left ventricular mass correlated with plasma C16 : 0/C24 : 0, but this relationship became nonsignificant after adjustment for multiple comparisons. Decreased left atrial function and increased left atrial size also related to C16 : 0/C24 : 0. Furthermore, increased incident heart failure, overall cardiovascular disease (CVD) mortality and all-cause mortality were associated with higher C16 : 0/C24 : 0 (or lower C24 : 0/C16 : 0). Finally, a number of possible biological mechanisms are outlined supporting the link between C16 : 0/C24 : 0 ceramides, ceramide signalling and CVD. High cardiac levels of total ceramides are noted in heart failure. In the plasma, C16 : 0/C24 : 0 ceramides may be a valuable biomarker of preclinical left ventricular dysfunction, remodelling, heart failure and mortality. Continued exploration of the mechanisms underlying these profound relationships may help develop specific lipid modulators to combat cardiac dysfunction and heart failure.

Identifying and triangulating all available evidence on the effect of blood lipids and statins on dementia outcomes

AbstractBackgroundMuch published literature exists on the effect of blood lipid levels, and lipid‐regulating agents (LRA) such as statins, on the risk of dementia and related outcomes. Several approaches, including observational studies, randomised controlled trials (RCTs) and Mendelian randomisation (MR) studies (which uses genetic variants as proxies for the risk factor of interest) have been used to try and address this question, each with distinct assumptions and limitations. However, no previous review has sought to systematically identify and integrate these distinct study designs as part of a single synthesis exercise. This comprehensive systematic review and qualitative triangulation of the evidence aims to address this.MethodFollowing standard systematic review methods, 16109 potentially eligible records were identified by a systematic search and screened as part of the review. Of these, 127 records reporting 105 primary studies were included, the majority of which (n=92; ∼88%) were observational studies. Data were extracted using a piloted form, and the risk of bias in included studies was assessed using the appropriate domain‐based tool (e.g. ROBINS‐I for non‐randomised studies of interventions).ResultDistinct study designs were only available for some exposure (lipids/statins) and outcome (all‐cause dementia, Alzheimer’s disease, vascular dementia) pairs. A common theme across study designs was the absence of vascular dementia outcomes.A key example of the triangulation approach if the results for the effect of statins on all‐cause dementia. Evidence from the meta‐analysis of observational studies found a protective effect (HR: 0.78, 95%CI: 0.69‐0.89), in contrast to both the RCT (OR:1, 95%CI: 0.60‐1.65) and MR (RR:0.9, 95%CI: 0.29‐2.83) approaches. This discrepancy could potentially be explained by immortal time bias, which typically increases the observed protective effect of the intervention, as several observational studies were found to suffer from this bias.ConclusionEvidence on the effect of blood lipid levels, and lipid modifying agents, is available from study with distinct methodological designs. By identifying and integrating this evidence as part of a single synthesis exercise, the strength of the conclusions can be increased. Future research should specifically focus on vascular dementia as an outcome, as there is a lack of evidence on this condition.

Abstract 13470: Update on Lipid Profiles and Lipid Modifying Therapies in Heart Transplant Recipients, a Single Center Experience

Introduction: Statin use after heart transplant (HT) has been shown to reduce rates of CAV and improve morbidity and mortality regardless of lipid profile. However, drug-drug interactions (DDIs) between statins and immunosuppressive therapies limit their use, particularly at higher doses. Recently, non-statin lipid modifying therapies have also been used in the HT population, despite a lack of outcome trials. Objective: We sought to examine current trends in lipid profiles and lipid-lowering therapy use in the HT population. Methods: We performed a retrospective chart review of 198 HT recipients (average age 53.6 years, 139 males, 59 females) transplanted between 4/8/2016 and 3/24/2020 at a single center. Of those patients, 82 underwent HT for ischemic cardiomyopathy (ICM), and 116 underwent HT for nonischemic cardiomyopathy (NICM). Lipid panels and medications were collected pre-transplant, immediately post-transplant, and 1-year post-transplant. Most recent values were also collected. At each point the 2018 lipid guidelines were used to determine the recommended intensity of statin each patient should ideally be on if they were not transplant patients. Results: Median cholesterol, triglyceride, HDL, and LDL values were reasonably well-controlled post HT. Despite high overall rates of statin use, our data suggest that most HT recipients are on lower than guideline-recommended statin doses due to DDI, particularly in the ICM group. The proportion of patients on non-statin lipid modifying therapies increased over time. Conclusions: There is emerging evidence that non-statin therapies added to statins can further reduce atherothrombotic events in non-transplant patients. These therapies may offer options for additional lipid control in transplant recipients whose statin use is limited by DDIs. However, the pathophysiology of CAV and atherosclerosis are different, and outcome trials of non-statin lipid therapies in HT patients are urgently needed.

Sphingomyelin Phosphodiesterase Acid-Like 3b is Essential for Toll-Like Receptor 3 Signaling in Human Podocytes.

Recent studies have revealed the importance of cell membrane stability in normal cell function. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), a lipid modifying enzyme that converts sphingomyelin to ceramide in the cell membrane, is expressed in macrophages and regulates Toll-like receptor (TLR) 4 signaling by altering cell membrane fluidity. SMPDL3b is also expressed in human podocytes, which are involved in the pathogenesis of several glomerular diseases such as diabetic kidney disease, focal segmental glomerulosclerosis, and idiopathic nephrotic syndrome in children; however, the role of SMPDL3b in podocyte innate immunity is unclear. As podocytes are equipped with innate immune systems including TLR3, and viral infections often exacerbate proteinuria in children with idiopathic nephrotic syndrome, we hypothesized that changes in SMPDL3b expression levels could affect anti-viral responses via TLR3 signaling in podocytes, consequently impairing normal podocyte function. To examine the role of SMPDL3b in TLR3 signaling in podocytes, we treated conditionally immortalized human podocytes with polyinosinic-polycytidylic acid (poly IC), to activate TLR3 signaling. The cells were then transfected with small interfering RNA against SMPDL3b. Poly IC activated the TLR3 pathway, whereas knockdown of SMPDL3b attenuated poly IC-induced interferon-β/chemokine C-X-C ligand 10 expression in podocytes. To our knowledge, this is the first report demonstrating SMPDL3b involvement in podocyte innate immunity; these results suggest that SMPDL3b is essential for adequate anti-viral responses in podocytes, possibly by modulating lipid metabolism in the cell membrane.

Pathophysiological principles of dyslipoproteinaemia

The effective reduction of atherogenic lipoproteins has contributed to the rate of atherosclerosis-related cardiovascular complications being approximately halved over the last 50 years. Nevertheless, cardiovascular disease will be the leading cause of death worldwide in the coming years. The focus of this review is on the clinical significance of the pathophysiology of changes in lipid and lipoprotein metabolism. Elevated levels of atherogenic lipoproteins are a causal risk factor for atherosclerotic cardiovascular disease. Primary forms of hypercholesterolaemia have a significantly higher ASCVD risk because of the already lifelong LDL elevation (higher cumulative LDL exposure for the vessel wall). Secondary changes in lipid and lipoprotein metabolism (e. g. in diabetes or hypothyroidism) must be excluded or treated. Regulatory key steps in the pathophysiology of lipid metabolism and atherosclerotic plaque are "drug targets" for existing and new lipid and lipoprotein modifying therapies.

Membrane remodelling and triacylglycerol accumulation in drought stress resistance: The case study of soybean phospholipases A

Agriculture is facing major constraints with the increase of global warming, being drought a major factor affecting productivity. Soybean (Glycine max) is among the most important food crops due to the high protein and lipid content of its seeds despite being considerably sensitive to drought. Previous knowledge has shown that drought induces a severe modulation in lipid and fatty acid content of leaves, related to alteration of membrane structure by lipolytic enzymes and activation of signalling pathways. In that sense, little is known on lipid modulation and lipolytic enzymes’ role in soybean drought stress tolerance. In this work, we present for the first time, soybean leaves lipid content modulation in several drought stress levels, highlighting the involvement of phospholipases A. Moreover, a comprehensive analysis of the phospholipase A superfamily was performed, where 53 coding genes were identified and 7 were selected to gene expression analysis in order to elucidate their role in soybean lipid modulation under water deficit. Proportionally to the drought severity, our results revealed that galactolipids relative abundance and their content in linolenic acid decrease. At the same time an accumulation of neutral lipids, mainly due to triacylglycerol content increase, as well as their content in linolenic acid, is observed. Overall, PLA gene expression regulation and lipid modulation corroborate the hypothesis that phospholipases A may be channelling the plastidial fatty acids into extraplastidial lipids leading to a drought-induced accumulation of triacylglycerol in soybean leaves, a key feature to cope with water stress.

Targeting cholesterol homeostasis in hematopoietic malignancies

AbstractCholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation, and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation, and hematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis by either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials involving acute myeloid leukemia to test the combination of chemotherapy with drugs interfering with cholesterol synthesis (ie, statins). We review the role of cholesterol homeostasis in hematopoietic malignancies as well as in cells of the tumor microenvironment and discuss the potential use of lipid modulators for therapeutic purposes.

Prevalence of corneal arcus and associated factors in a German population-Results from the Gutenberg Health Study.

PurposeWe aimed to determine the prevalence of corneal arcus and to identify associated factors in the general population of Germany.MethodsThe Gutenberg Health Study (GHS) is a population-based cohort study in Germany, which includes an ophthalmological assessment. Refraction, distance-corrected visual acuity, non-contact tonometry and anterior segment imaging were performed for the five-year follow-up examination. Anterior segment photographs were graded for the presence of corneal arcus. Prevalence estimates were computed, and multivariable logistic regression analysis was applied to determine associated factors for corneal arcus including sex, age, spherical equivalent, central corneal thickness, intraocular pressure (IOP), socio-economic status, smoking, BMI, systolic and diastolic arterial blood pressure, HbA1c, HDL-C, LDL-C, triglyceride, and lipid modifying agents.ResultsA total of 9,850 right and 9,745 left eyes of 9,858 subjects (59.2±10.8 years), 49.0% females were included in this cross-sectional analysis. 21.1% of men (95%-CI: 20.0%– 22.3%) had a corneal arcus in at least one eye, and 16.9% (95%-CI: 15.9%– 18.0%) of women. In multivariable analyses, the presence of corneal arcus was associated with male gender (OR = 0.54 for female, p<0.0001), higher age (OR = 2.54 per decade, p<0.0001), smoking (OR = 1.59, p<0.0001), hyperopia (OR = 1.05 per diopter, p<0.0001), thinner cornea (OR = 0.994 per μm, p<0.0001), higher IOP (OR = 1.02, p = 0.039), higher HDL-C-level (OR = 2.13, p<0.0001), higher LDL-C-level (OR = 1.21, p<0.0001), and intake of lipid modifying agents (OR = 1.26, p = 0.0001). Arcus was not associated with socio-economic status, BMI, arterial blood pressure, and HbA1c.ConclusionsCorneal arcus is a frequent alteration of the cornea in Germany and is associated with ocular parameters and systemic parameters of dyslipidemia.

Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease

Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.

StAR-Related Lipid Transfer (START) Domains Across the Rice Pangenome Reveal How Ontogeny Recapitulated Selection Pressures During Rice Domestication.

The StAR-related lipid transfer (START) domain containing proteins or START proteins, encoded by a plant amplified family of evolutionary conserved genes, play important roles in lipid binding, transport, signaling, and modulation of transcriptional activity in the plant kingdom, but there is limited information on their evolution, duplication, and associated sub- or neo-functionalization. Here we perform a comprehensive investigation of this family across the rice pangenome, using 10 wild and cultivated varieties. Conservation of START domains across all 10 rice genomes suggests low dispensability and critical functional roles for this family, further supported by chromosomal mapping, duplication and domain structure patterns. Analysis of synteny highlights a preponderance of segmental and dispersed duplication among STARTs, while transcriptomic investigation of the main cultivated variety Oryza sativa var. japonica reveals sub-functionalization amongst genes family members in terms of preferential expression across various developmental stages and anatomical parts, such as flowering. Ka/Ks ratios confirmed strong negative/purifying selection on START family evolution, implying that ontogeny recapitulated selection pressures during rice domestication. Our findings provide evidence for high conservation of START genes across rice varieties in numbers, as well as in their stringent regulation of Ka/Ks ratio, and showed strong functional dependency of plants on START proteins for their growth and reproductive development. We believe that our findings advance the limited knowledge about plant START domain diversity and evolution, and pave the way for more detailed assessment of individual structural classes of START proteins among plants and their domain specific substrate preferences, to complement existing studies in animals and yeast.

Cannabis sativa and/or melatonin do not alter brain lipid but alter oxidative mechanisms in female rats

BackgroundLipid profile and redox status play a role in brain (dys)functions. Cannabinoid and melatonergic systems operate in the brain and contribute to brain (patho)physiology, but their roles in the modulation of brain lipid and redox status are not well-known. We studied the effect of ethanol extract of Cannabis sativa (CS) and/or melatonin (M) on the lipid profile and anti-oxidant system of the rat brain.MethodsWe randomly divided twenty-four (24) female Wistar rats into 4 groups (n = 6 rats each). Group 1 (control) received distilled water mixed with DMSO. Groups II–IV received CS (2 mg/kg), M (4 mg/kg), and co-administration of CS and M (CS + M) respectively via oral gavage between 8:00 am and 10:00 am once daily for 14 days. Animals underwent 12-h fasting after the last day of treatment and sacrificed under ketamine anesthesia (20 mg/kg; i.m). The brain tissues were excised and homogenized for assay of the concentrations of the total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein cholesterol (HDL-C), nitric oxide (NO), malondialdehyde (MDA), and the activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and acetylcholinesterase (AChE). One-way analysis of variance (ANOVA) was used to compare means across groups, followed by the least significant difference (LSD) post-hoc test.ResultsCS and/or M did not affect the lipid profile parameters. However, CS increased the G6PD (from 15.58 ± 1.09 to 21.02 ± 1.45 U/L; p = 0.047), GPx (from 10.47 ± 0.86 to 17.71 ± 1.04 U/L; p = 0.019), and SOD (from 0.81 ± 0.02 to 0.90 ± 0.01 μM; p = 0.007), but decreased NO (from 9.40 ± 0.51 to 6.75 ± 0.21 μM; p = 0.010) and had no effect on MDA (p = 0.905), CAT (p = 0.831), GR (p = 0.639), and AChE (p = 0.571) in comparison with the control group. M augmented the increase in G6PD (from 21.02 ± 1.45 U/L to 27.18 ± 1.81 U/L; p = 0.032) and decrease in NO (from 6.75 ± 0.21 to 4.86 ± 0.13 μM; p = 0.034) but abolished the increase in GPx (from 17.71 ± 1.04 to 8.59 ± 2.06 U/L; p = 0.006) and SOD (from 0.90 ± 0.01 to 0.70 ± 0.00 μM; p = 0.000) elicited by CS in the rat brain in comparison with the CS group.ConclusionsCS and M do not alter brain lipid profile. Our data support the contention that CS elicits an anti-oxidative effect on the brain tissue and that CS + M elicits a pro-oxidant effect in rat brain.

Modulation of lipid metabolism through multiple pathways during oocyte maturation and embryo culture in bovine.

Lipid accumulation occurs in cultured embryos and is associated with reduced cryotolerance. Here we report the use of a multiple pathway lipid modulator cocktail (l-carnitine, linoleic acid and forskolin) to improve cryosurvival. First, we stained oocytes and embryos with Oil Red to examine the time course of lipid accumulation during in vitro fertilization (IVF) and embryo culture. Then we evaluated the effects of the lipid modulators cocktail on lipid content, developmental rates and survival after vitrification. In our conditions, lipid accumulation was detected (P < 0.05) at the end of in vitro maturation (IVM) and after 4 days of embryo culture (D4-D5). In experiment 1, we used lipid modulator cocktail during IVM. Reduced (P < 0.05) lipid accumulation was detected in oocytes (Control: 49.9 ± 1.6, Lip. Mod. IVM: 45.0 ± 1.8) but no changes were present at blastocyst stage (Control: 62.4 ± 2.6, Lip. Mod. IVM: 66.8 ± 2.7). Treated oocytes presented decreased (P < 0.05) blastocyst rates and lower (P < 0.05) re-expansion after vitrification. In experiment 2, lipid modulators cocktail was used during embryo culture (from D4-D7 or D6-D7). Treatment had an effect on lipid metabolism, as lipid content was increased (P < 0.05) in D7 blastocysts in treated groups (Control: 52.7 ± 3.1a, D4: 65.9 ± 2.6b, D6: 78.1 ± 2.7b). However, no effect was present for cleavage, blastocyst and cryosurvival rates. No difference was detected in mean cell number comparing the three groups (Control: 78.9 ± 9.6, D4: 82.6 ± 16.5, D6: 68.3 ± 7.8), but apoptosis rate was increased (P < 0.05) in vitrified-warmed blastocysts from treated groups (Control: 14.77*, D4: 22.28, D6: 22.22). We concluded that the combined use of lipid modulators was efficient to promote changes in lipid content of oocytes and embryos in bovine, but those changes did not reflect positively on embryo development or cryosurvival.

Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria.

Colistin regained global interest as a consequence of the rising prevalence of multidrug-resistant Gram-negative Enterobacteriaceae. In parallel, colistin-resistant bacteria emerged in response to the unregulated use of this antibiotic. However, some Gram-negative species are intrinsically resistant to colistin activity, such as Neisseria meningitides, Burkholderia species, and Proteus mirabilis. Most identified colistin resistance usually involves modulation of lipid A that decreases or removes early charge-based interaction with colistin through up-regulation of multistep capsular polysaccharide expression. The membrane modifications occur by the addition of cationic phosphoethanolamine (pEtN) or 4-amino-l-arabinose on lipid A that results in decrease in the negative charge on the bacterial surface. Therefore, electrostatic interaction between polycationic colistin and lipopolysaccharide (LPS) is halted. It has been reported that these modifications on the bacterial surface occur due to overexpression of chromosomally mediated two-component system genes (PmrAB and PhoPQ) and mutation in lipid A biosynthesis genes that result in loss of the ability to produce lipid A and consequently LPS chain, thereafter recently identified variants of plasmid-borne genes (mcr-1 to mcr-10). It was hypothesized that mcr genes derived from intrinsically resistant environmental bacteria that carried chromosomal pmrC gene, a part of the pmrCAB operon, code three proteins viz. pEtN response regulator PmrA, sensor kinase protein PmrAB, and phosphotransferase PmrC. These plasmid-borne mcr genes become a serious concern as they assist in the dissemination of colistin resistance to other pathogenic bacteria. This review presents the progress of multiple strategies of colistin resistance mechanisms in bacteria, mainly focusing on surface changes of the outer membrane LPS structure and other resistance genetic determinants. New handier and versatile methods have been discussed for rapid detection of colistin resistance determinants and the latest approaches to revert colistin resistance that include the use of new drugs, drug combinations and inhibitors. Indeed, more investigations are required to identify the exact role of different colistin resistance determinants that will aid in developing new less toxic and potent drugs to treat bacterial infections. Therefore, colistin resistance should be considered a severe medical issue requiring multisectoral research with proper surveillance and suitable monitoring systems to report the dissemination rate of these resistant genes.