scholarly journals Influence of Cholesterol on the Orientation of the Farnesylated GTP-bound KRas-4B Binding with Anionic Model Membranes

2020 ◽  
Author(s):  
Huixia Lu ◽  
Jordi Martí
Keyword(s):  
Signal Transduction ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Plasma Cholesterol ◽  
Cholesterol Content ◽  
Extensive Study ◽  
Distribution Functions ◽  
Model Membranes ◽  
High Cholesterol ◽  
Cholesterol Intake

The Ras family of proteins is tethered to the inner leaflet of the cell membranes which play an essential role in signal transduction pathways that promote cellular proliferation, survival, growth, and differentiation. KRas-4B, the most mutated Ras isoform in different cancers, has been under extensive study for more than two decades. Here we have focused our interest on the influence of cholesterol on the orientations that KRas-4B adopts with respect to the plane of the anionic model membranes. How cholesterol in the bilayer might modulate preferences for specific orientation states is far from clear. Herein, after analyzing data from in total 4000 ns-long MD simulations for four KRas-4B systems, properties such as the area per lipid and thickness of the membrane as well as selected radial distribution functions, penetration of different moieties of KRas-4B, and internal conformational fluctuations of flexible moieties in KRas-4B have been calculated. It has been shown that high cholesterol content in the PM favors OS1, exposing the effector-binding loop for signal transduction in the cell from the atomic level. We confirm that high cholesterol in the PM helps KRas-4B mutant stay in its constitutively active state, which suggests that high cholesterol intake can increase mortality and may promote cancer progression for cancer patients. We propose that during the treatment of KRas-4B-related cancers, reducing the cholesterol level in the PM and sustaining cancer progression by controlling the plasma cholesterol intake might be taken into account in anti-cancer therapies.

scholarly journals Influence of Cholesterol on the Orientation of the Farnesylated GTP-Bound KRas-4B Binding with Anionic Model Membranes

Membranes ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 364
Author(s):  
Huixia Lu ◽  
Jordi Martí
Keyword(s):  
Signal Transduction ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Plasma Cholesterol ◽  
Cholesterol Content ◽  
Extensive Study ◽  
Distribution Functions ◽  
Model Membranes ◽  
High Cholesterol ◽  
Cholesterol Intake

The Ras family of proteins is tethered to the inner leaflet of the cell membranes which plays an essential role in signal transduction pathways that promote cellular proliferation, survival, growth, and differentiation. KRas-4B, the most mutated Ras isoform in different cancers, has been under extensive study for more than two decades. Here we have focused our interest on the influence of cholesterol on the orientations that KRas-4B adopts with respect to the plane of the anionic model membranes. How cholesterol in the bilayer might modulate preferences for specific orientation states is far from clear. Herein, after analyzing data from in total 4000 ns-long molecular dynamics (MD) simulations for four KRas-4B systems, properties such as the area per lipid and thickness of the membrane as well as selected radial distribution functions, penetration of different moieties of KRas-4B, and internal conformational fluctuations of flexible moieties in KRas-4B have been calculated. It has been shown that high cholesterol content in the plasma membrane (PM) favors one orientation state (OS1), exposing the effector-binding loop for signal transduction in the cell from the atomic level. We confirm that high cholesterol in the PM helps KRas-4B mutant stay in its constitutively active state, which suggests that high cholesterol intake can increase mortality and may promote cancer progression for cancer patients. We propose that during the treatment of KRas-4B-related cancers, reducing the cholesterol level in the PM and sustaining cancer progression by controlling the plasma cholesterol intake might be taken into account in anti-cancer therapies.

scholarly journals Impact of high cholesterol intake on tissue cholesterol content and lipid transfers to high-density lipoprotein

Nutrition ◽  
2011 ◽  
Vol 27 (6) ◽  
pp. 713-718 ◽  
Author(s):  
Tatiane V. Oliveira ◽  
Fernanda Maniero ◽  
Marília H.H. Santos ◽  
Sérgio P. Bydlowski ◽  
Raul C. Maranhão
Keyword(s):  
High Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
High Density ◽  
High Cholesterol ◽  
Cholesterol Intake ◽  
Tissue Cholesterol

scholarly journals The effect of treatment conditions on color characteristics and measure of cholesterol removal from milk by beta-cyclodextrin application

10.5219/1557 ◽  
2021 ◽  
Vol 15 ◽  
pp. 192-198
Author(s):  
Lukáš Kolarič ◽  
Peter Šimko
Keyword(s):  
Large Scale ◽  
Mixing Time ◽  
Cholesterol Content ◽  
High Cholesterol ◽  
Cholesterol Removal ◽  
Mixing Speed ◽  
Treatment Conditions ◽  
Cholesterol Intake ◽  
Effect Of Treatment

Long-term high cholesterol intake is one of the most critical risk factors of cardiovascular diseases (CVD). As milk and dairy products are rich in cholesterol and are consumed on a large scale, the production of low-cholesterol content products could decrease effectively high cholesterol intake what would be one of the crucial steps in CVD prevention. Thus, this study is aimed at optimization of treatment conditions (mixing speed, time, and temperature) and β-cyclodextrin addition affecting the measure of cholesterol removal in milk. As found, the optimal conditions were identified such as mixing speed 840 rpm, mixing time 10 min, and the temperature of mixing 25 °C while the most effectivity in cholesterol decrease content (98.1%) was observed after 2.0% β-cyclodextrin addition. The cholesterol removal process did not affect considerably the lightness values L* of treated milk, slight differences were noticed in terms of a* and b* color values but ΔE values were statistically insignificant, i.e., the process of cholesterol removal did not affect visual characteristics of treated milk. So, these conditions can be applied for the production of milk base functional foods with the decreased cholesterol content.

scholarly journals Effects of a low-energy diet associated with egg supplementation on plasma cholesterol and lipoprotein levels in normal subjects: results of a cross-over study

1986 ◽  
Vol 56 (3) ◽  
pp. 561-575 ◽  
Author(s):  
Christiane R. Lacombe ◽  
Geneviève R. Corraze ◽  
Maryse M. Nibbelink ◽  
Danièle Boulze ◽  
Philippe Douste-Blazy ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Energy ◽  
Low Density ◽  
High Cholesterol ◽  
Dietary Regimen ◽  
Cholesterol Intake ◽  
Usual Diet ◽  
Low Energy Diet

1. The influence of a low-energy diet when associated with high-cholesterol intake was investigated in seventeen normal men during an 8-week cross-over study. The subjects were given a daily supplement of two whole eggs and two egg yolks (approximately 1 g cholesterol) either with their usual diet for 4 weeks or with a low-energy diet for 4 weeks. Each subject took part randomly in both dietary periods.2. During the first part of the study, no changes occurred in the plasma cholesterol of the subjects with egg supplementation of the usual diet.3. In contrast, the low-energy diet and associated weight loss markedly decreased the tolerance to high- cholesterol intake resulting in increased plasma cholesterol. The mean rise was 22.7% but with wide individual variations in the response. This was almost completely normalized when the subjects returned to their usual energy intake indicating the involvement of weight reduction in the increase observed.4. Changes in low-density-lipoprotein (LDL) cholesterol were parallel to those of total plasma cholesterol with an increase following the low-energy diet and normalization after body-weight recovery.5. The opposite effect was shown with the low-energy diet after previous adaptation to the consumption of four eggs per day. This dietary regimen resulted in a decrease in plasma cholesterol although it was not significant. Moreover, the lipoprotein profile was improved with a decrease in very-low-density-lipoprotein (VLDL) cholesterol and an increase in high-density-lipoprotein (HDL) cholesterol.6. High-cholesterol intake induced significant changes in lipoprotein composition whatever the energy ration. LDL and HDL were enriched in cholesterol esters as early as the 1st month of egg supplementation of the diet.7. Taken together, the results emphasize the possible adverse effect of slimming diets when associated with high-cholesterol intake. The existence of ‘high-responders’ to these dietary conditions calls for special attention to be paid to the cholesterol content of restricted diets.

MAPK Cascades in Cell Growth and Death

Physiology ◽  
1997 ◽  
Vol 12 (6) ◽  
pp. 286-293 ◽  
Author(s):  
JT Neary
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Cellular Proliferation ◽  
Inflammatory Diseases ◽  
Growth Arrest ◽  
Therapeutic Strategies ◽  
Extracellular Signals ◽  
Mapk Cascades ◽  
Proliferation And Differentiation ◽  
Signaling Components

Distinct signal transduction cascades comprised of at least three proteinkinases mediate cellular proliferation and differentiation, growth arrest, and programmed cell death. These cytosolic enzymes relay extracellular signals from cell surface to nucleus, leading to changes in gene expression. Signaling components of these cascades offer new possibilities for therapeutic strategies in tumorigenesis, inflammatory diseases, immunopotentiation, wound healing, and regeneration.

scholarly journals lncRNA NORAD Contributes to Colorectal Cancer Progression by Inhibition of miR-202-5p

2018 ◽  
Vol 26 (9) ◽  
pp. 1411-1418 ◽  
Author(s):  
Jie Zhang ◽  
Xiao-Yan Li ◽  
Ping Hu ◽  
Yuan-Sheng Ding
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Competing Endogenous Rna

Previous study indicates that long noncoding RNA NORAD could serve as a competing endogenous RNA to pancreatic cancer metastasis. However, its role in colorectal cancer (CRC) needs to be investigated. In the present study, we found that the expression of NORAD was significantly upregulated in CRC tissues. Furthermore, the expression of NORAD was positively related with CRC metastasis and patients’ poor prognosis. Knockdown of NORAD markedly inhibited CRC cell proliferation, migration, and invasion but induced cell apoptosis in vitro. In vivo experiments also indicated an inhibitory effect of NORAD on tumor growth. Mechanistically, we found that NORAD served as a competing endogenous RNA for miR-202-5p. We found that there was an inverse relationship between the expression of NORAD and miR-202-5p in CRC tissues. Moreover, overexpression of miR-202-5p in SW480 and HCT116 cells significantly inhibited cellular proliferation, migration, and invasion. Taken together, our study demonstrated that the NORAD/miR-202-5p axis plays a pivotal function on CRC progression.

scholarly journals Effects of ChREBP deficiency on adrenal lipogenesis and steroidogenesis

2021 ◽  
Author(s):  
Ken Takao ◽  
Katsumi Iizuka ◽  
Yanyan Liu ◽  
Teruaki Sakurai ◽  
Sodai Kubota ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Target Genes ◽  
Adrenal Glands ◽  
Plasma Cholesterol ◽  
Steroid Hormone ◽  
Acid Synthesis ◽  
Cholesterol Content ◽  
Hormone Synthesis ◽  
Corticosterone Secretion ◽  
Element Binding Protein

Carbohydrate response element binding protein (ChREBP) is critical in the regulation of fatty acid and triglyceride synthesis in the liver. Interestingly, Chrebp-/- mice show reduced levels of plasma cholesterol, which is critical for steroid hormone synthesis in adrenal glands. Furthermore, Chrebp mRNA expression was previously reported in human adrenal glands. Thus, it remains to be investigated whether ChREBP plays a role directly or indirectly in steroid hormone synthesis and release in adrenal glands. In the present study, we find that Chrebp mRNA is expressed in mouse adrenal glands and that ChREBP binds to carbohydrate response elements. Histological analysis of Chrebp-/- mice shows no adrenal hyperplasia and less oil red O staining compared with that in wild-type mice. In adrenal glands of Chrebp-/- mice, expression of Fasn and Scd1, two enzymes critical for fatty acid synthesis, was substantially lower and triglyceride content was reduced. Expression of Srebf2, a key transcription factor controlling synthesis and uptake of cholesterol and the target genes was upregulated, while cholesterol content was not significantly altered in the adrenal glands of Chrebp-/- mice. Adrenal corticosterone content and plasma adrenocorticotropic hormone and corticosterone levels were not significantly altered in Chrebp-/- mice. Consistently, expression of genes related to steroid hormone synthesis was not altered. Corticosterone secretion in response to two different stimuli, namely 24-h starvation and cosyntropin administration, were also not altered in Chrebp-/- mice. Taking these results together, corticosterone synthesis and release were not affected in Chrebp-/- mice despite reduced plasma cholesterol levels.

scholarly journals “Cholesterogenic" dietary factors and milk and milk fat yields in dairy cows

1959 ◽  
Vol 31 (1) ◽  
pp. 1-10
Author(s):  
Pellervo Saarinen
Keyword(s):  
Milk Yield ◽  
Milk Fat ◽  
Partial Correlation ◽  
Plasma Cholesterol ◽  
Live Weight ◽  
Cholesterol Content ◽  
Dietary Factors ◽  
Experimental Results ◽  
Fat Intake ◽  
Crude Fibre

The following results have been obtained from a statistical investigation carried out on experimental results from 27 feeding trials in which the effect of cholesterogenic dietary factors, observed in an earlier investigation (5), on the relative levels of milk and milk fat yields are compared. An execessive intake of energy either has no statistically clear effect on the level of yield, or the effect is negative. In this respect the results obtained are uniform with experimental results obtained in Norway and Denmark using other methods (1, 6). In the negative cases the effect appears more clearly in the level of milk and milk fat yields than in the plasma cholesterol content. An excessive intake of protein shows a negative effect only in well-conditioned obese cows. An increase of the proportion of digestible crude fibre in the food ration appears in most cases to have an increasing effect on the milk yield. This effect, however, seems to be slighter than the effect on the blood plasma cholesterol content. The level of milk and milk fat yields has proved to be statistically in positive partial correlation to the digestible crude fat intake in g/kg live weight ,and in negative partial correlation to the relative fat intake compared with the nutritional requirements of the animal. This indicates that the favourable level of fat intake varies according to the level of milk yield, being larger in stages of higher yields than in stages of small yields.

Use of Medium Potency Statins Is Associated with Improved Outcomes after Frontline RCHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-45
Author(s):  
Sushanth Gouni ◽  
Paolo Strati ◽  
Jason Westin ◽  
Loretta J. Nastoupil ◽  
Raphael E Steiner ◽  
...  
Keyword(s):  
Cell Lines ◽  
Research Funding ◽  
Response Assessment ◽  
Cholesterol Content ◽  
In Vivo Studies ◽  
High Cholesterol ◽  
Improved Outcomes ◽  
Significant Difference

Background: Pre-clinical studies show that statins may improve the efficacy of chemoimmunotherapy in patients with DLBCL, through interference with cell membrane-initiated signaling pathways. Clinical retrospective studies, however, yield conflicting data, due to heterogeneous properties of statins, including potency and hydrophilicity. Methods: This is a retrospective analysis of patients with previously untreated, advanced stage DLBCL, non-double hit, treated with frontline R-CHOP between 01/01/2000 and 09/01/2019 (data cut-off 04/15/2020) at MD Anderson Cancer Center, and for whom data regarding statin use at time of initiation of treatment were available. Lugano 2014 response criteria were applied retrospectively for response assessment. Cellular cholesterol levels were analyzed in 6 DLBCL cell lines using an Amplex red fluorometric assay. A doxorubicin (DXR)-resistant cell line was generated exposing SUDHL4 cells to escalating doses of DXR; a DXR-resistant DLBCL patient-derived xenograft (PDX) model was established through serial transplantation and exposure to DXR. Results: 271 patients were included in the analysis, 182 (67%) were older than 60 years, 134 (49%) were male, 212 (72%) had stage IV disease, and 217 (80%) had an IPI score > 3; upon pathological review, 38 (36%) cases were non-GCB type, and 18 (28%) were double-expressors; 214 (79%) were able to complete all planned 6 cycles of RCHOP. Seventy-nine (29%) patients received statins at time of initiation of chemoimmunotherapy: 15 patients received low potency statin, 51 medium and 13 high; 18 patients received hydrophilic statins and 61 lipophilic. Patients receiving statins were significantly older as compared to patients who did not (p<0.001); no other significant difference in baseline characteristics was observed when comparing the 2 groups. Overall, 265 out of 271 patients were evaluable for response, as 6 stopped treatment because of toxicity before first response assessment. Among these, ORR was 95% (252/265) and CR rate was 62% (165/265). ORR rate was identical in patients who were treated with statin and those who did not (95% both, p=1). After a median follow-up of 77 months (95% CI, 70-84 months), 119 patients progressed/died, median PFS was not reached and 6-year PFS was 57%. 6-year PFS rate according to statin intensity was: 48% (low), 72% (medium), 57% (high). PFS. 6-year PFS rate was 64% for hydrophilic and 72% for lipophilic statins. Patients treated with statins had a trend for longer PFS (p=0.06), significantly longer for patients receiving medium potency statins (p=0.04). No significant difference in PFS was observed when comparing patients treated with lipophilic statins to all others (not reached vs 84 months, p=0.22). To confirm these clinical data, in-vitro and in-vivo studies were performed. Six cell lines were tested: 4 with high cholesterol content (SUDHL4, HBL1, HT, and U2932; 5.0-8.0 µg/mg protein), and 2 with low cholesterol content (DOHH2 and OCI-LY19; 1.5-2.0 µg/mg protein); the latter showed the highest sensitivity to DXR-mediated killing. The combination of lovastatin and DXR (10nM) was tested in all 4 cell lines with high cholesterol content, resulting in more cell death than either treatment alone. Lovastatin (at the nanomolar range) resensitized DXR-resistant SUDHL4 cells to DXR. Finally, in a DXR-resistant PDX model, the combination of lovastatin and DXR resulted in delayed tumor growth as compared to chemotherapy alone. Conclusions: Use of medium potency statins is associated with improved outcomes after frontline RCHOP in patients with DLBCL. This was further confirmed in functional in-vitro and in-vivo studies. Future interventional studies, aimed at improving outcomes in these patients using this novel combination, are warranted. Disclosures Westin: Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Nastoupil:Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria. Neelapu:Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Karus Therapeutics: Research Funding; N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Calibr: Other; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding. Landgraf:NCI/NIH: Research Funding. Vega:NCI: Research Funding.

Hypercholesterolemia of total starvation: its mechanism via tissue mobilization of cholesterol

1975 ◽  
Vol 229 (2) ◽  
pp. 365-369 ◽  
Author(s):  
JC Swaner ◽  
WE Connor
Keyword(s):  
Adipose Tissue ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Specific Radioactivity ◽  
Cholesterol Content ◽  
Cholesterol Concentration ◽  
Tissue Cell ◽  
Adipose Tissue Cell ◽  
Total Starvation ◽  
Linear Decay

After the establishment of a relatively linear decay curve for plasma [4-14C]cholesterol, rabbits were starved for 26-32 days. The plasma cholesterol concentration increased 400% during starvation. Concurrently, the plasma triglyceride level declined by 50%. While the plasma cholesterol was rising, the cholesterol specific radioactivity of the plasma remained unchanged in starved animals, but in control animals the plasma cholesterol specific radioactivity declined substantially. The cholesterol content of the liver and adipose tissue increased with starvation. The cholesterol specific radioactivities relative to plasma for adipose tissue were lower in the starved animals versus controls. These results support the hypothesis that cholesterol stored in the lipid droplet of the adipose tissue cell is released into plasma and is the chief source of the hypercholesterolemia observed during complete caloric starvation. Cholesterol metabolism in the starved animal can be depicted as a virtually closed system in both the input from biosynthesis and diet being low or zero and the output likewise being close to zero.

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