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1.
Lipids Health Dis ; 21(1): 5, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996476

RESUMO

Recent advances in society have resulted in the emergence of both hyperlipidemia and obesity as life-threatening conditions in people with implications for various types of diseases, such as cardiovascular diseases and cancer. This is further complicated by a global rise in the aging population, especially menopausal women, who mostly suffer from overweight and bone loss simultaneously. Interestingly, clinical observations in these women suggest that osteoarthritis may be linked to a higher body mass index (BMI), which has led many to believe that there may be some degree of bone dysfunction associated with conditions such as obesity. It is also common practice in many outpatient settings to encourage patients to control their BMI and lose weight in an attempt to mitigate mechanical stress and thus reduce bone pain and joint dysfunction. Together, studies show that bone is not only a mechanical organ but also a critical component of metabolism, and various endocrine functions, such as calcium metabolism. Numerous studies have demonstrated a relationship between metabolic dysfunction in bone and abnormal lipid metabolism. Previous studies have also regarded obesity as a metabolic disorder. However, the relationship between lipid metabolism and bone metabolism has not been fully elucidated. In this narrative review, the data describing the close relationship between bone and lipid metabolism was summarized and the impact on both the normal physiology and pathophysiology of these tissues was discussed at both the molecular and cellular levels.


Assuntos
Osso e Ossos/metabolismo , Metabolismo dos Lipídeos , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/fisiopatologia , Osso e Ossos/fisiologia , Osso e Ossos/fisiopatologia , Microambiente Celular/fisiologia , Colesterol/metabolismo , Colesterol/fisiologia , Humanos , Metabolismo dos Lipídeos/fisiologia , Osteoporose/metabolismo
2.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069902

RESUMO

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.


Assuntos
Carcinoma Hepatocelular/metabolismo , Colesterol/metabolismo , Fígado/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Colesterol/fisiologia , Feminino , Alemanha/epidemiologia , Hepacivirus/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/metabolismo , Hepatite C/virologia , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade
3.
Commun Biol ; 4(1): 779, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34163009

RESUMO

The Arabian camel (Camelus dromedarius) is the most important livestock animal in arid and semi-arid regions and provides basic necessities to millions of people. In the current context of climate change, there is renewed interest in the mechanisms that enable camelids to survive in arid conditions. Recent investigations described genomic signatures revealing evolutionary adaptations to desert environments. We now present a comprehensive catalogue of the transcriptomes and proteomes of the dromedary kidney and describe how gene expression is modulated as a consequence of chronic dehydration and acute rehydration. Our analyses suggested an enrichment of the cholesterol biosynthetic process and an overrepresentation of categories related to ion transport. Thus, we further validated differentially expressed genes with known roles in water conservation which are affected by changes in cholesterol levels. Our datasets suggest that suppression of cholesterol biosynthesis may facilitate water retention in the kidney by indirectly facilitating the AQP2-mediated water reabsorption.


Assuntos
Água Corporal/metabolismo , Camelus/fisiologia , Colesterol/fisiologia , Rim/metabolismo , Animais , Aquaporina 2/fisiologia , Desidratação/metabolismo , Clima Desértico , Metabolismo dos Lipídeos , Masculino , Proteoma , ATPase Trocadora de Sódio-Potássio/fisiologia , Transcriptoma
4.
Mol Biol Rep ; 48(5): 3945-3954, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34021444

RESUMO

Coronary artery disease (CAD) which is a complex cardiovascular disease is the leading cause of death worldwide. The changing prevalence of the disease in different ethnic groups pointing out the genetic background of CAD. In this study, we aimed to evaluate the contribution of selected cholesterol metabolism-related gene polymorphisms to CAD presence. A total of 493 individuals who underwent coronary angiography were divided into 2 groups: normal coronary arteries (≤ 30% stenosis) and critical disease (≥ 50% stenosis). Individuals were genotyped for APOC1 (rs11568822), APOD (rs1568565), LIPA (rs13500), SORL1 (rs2282649), and LDLR (rs5930) polymorphisms using hydrolysis probes in Real-Time PCR. Blood samples were drawn before coronary angiography and biochemical analyses were done. The results were statistically evaluated. When the study group was stratified according to CAD, the minor allele of APOD polymorphism was found related to decreased risk for T2DM in the non-CAD group. In logistic regression analysis adjusted for several confounders, LDLR rs5930 polymorphism was found associated with T2DM presence in the male CAD group [OR = 0.502, 95%CI (0.259-0.974), p = 0.042]. Besides, APOD and LIPA polymorphisms were shown to affect serum lipid levels in non-CAD T2DM patients (p < 0.05). The minor allele of APOC1 was found associated with triglyceride levels in males independent of CAD status. Besides, LDLR minor allele carrier females had elevated HbA1c and glucose levels independent from CAD status in the whole group. The cholesterol metabolism-related gene polymorphisms were found associated with T2DM and biochemical parameters stratified to sex, CAD, and T2DM status.


Assuntos
Colesterol/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus/genética , Idoso , Alelos , Apolipoproteína C-I/genética , Apolipoproteínas D/genética , Colesterol/fisiologia , Doença da Artéria Coronariana/complicações , Diabetes Mellitus/etiologia , Diabetes Mellitus/fisiopatologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genética , Fatores de Risco , Esterol Esterase/genética
5.
Endocrinology ; 162(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33784378

RESUMO

Two specialized functions of cholesterol during fetal development include serving as a precursor to androgen synthesis and supporting hedgehog (HH) signaling activity. Androgens are produced by the testes to facilitate masculinization of the fetus. Recent evidence shows that intricate interactions between the HH and androgen signaling pathways are required for optimal male sex differentiation and defects of either can cause birth anomalies indicative of 46,XY male variations of sex development (VSD). Further, perturbations in cholesterol synthesis can cause developmental defects, including VSD, that phenocopy those caused by disrupted androgen or HH signaling, highlighting the functional role of cholesterol in promoting male sex differentiation. In this review, we focus on the role of cholesterol in systemic androgen and local HH signaling events during fetal masculinization and their collective contributions to pediatric VSD.


Assuntos
Androgênios/biossíntese , Colesterol/fisiologia , Proteínas Hedgehog/metabolismo , Diferenciação Sexual/fisiologia , Transdução de Sinais/fisiologia , Animais , Colesterol/biossíntese , Transtornos do Desenvolvimento Sexual , Desenvolvimento Fetal/fisiologia , Feto/metabolismo , Humanos , Células Intersticiais do Testículo/fisiologia , Masculino , Testículo/embriologia , Testículo/metabolismo
6.
J Biol Chem ; 296: 100381, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33556372

RESUMO

Calcium-/voltage-gated, large-conductance potassium channels (BKs) control critical physiological processes, including smooth muscle contraction. Numerous observations concur that elevated membrane cholesterol (CLR) inhibits the activity of homomeric BKs consisting of channel-forming alpha subunits. In mammalian smooth muscle, however, native BKs include accessory KCNMB1 (ß1) subunits, which enable BK activation at physiological intracellular calcium. Here, we studied the effect of CLR enrichment on BK currents from rat cerebral artery myocytes. Using inside-out patches from middle cerebral artery (MCA) myocytes at [Ca2+]free=30 µM, we detected BK activation in response to in vivo and in vitro CLR enrichment of myocytes. While a significant increase in myocyte CLR was achieved within 5 min of CLR in vitro loading, this brief CLR enrichment of membrane patches decreased BK currents, indicating that BK activation by CLR requires a protracted cellular process. Indeed, blocking intracellular protein trafficking with brefeldin A (BFA) not only prevented BK activation but led to channel inhibition upon CLR enrichment. Surface protein biotinylation followed by Western blotting showed that BFA blocked the increase in plasmalemmal KCNMB1 levels achieved via CLR enrichment. Moreover, CLR enrichment of arteries with naturally high KCNMB1 levels, such as basilar and coronary arteries, failed to activate BK currents. Finally, CLR enrichment failed to activate BK channels in MCA myocytes from KCNMB1-/- mouse while activation was detected in their wild-type (C57BL/6) counterparts. In conclusion, the switch in CLR regulation of BK from inhibition to activation is determined by a trafficking-dependent increase in membrane levels of KCNMB1 subunits.


Assuntos
Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Células Musculares/metabolismo , Canais de Potássio/metabolismo , Animais , Canais de Cálcio/metabolismo , Membrana Celular/metabolismo , Artérias Cerebrais/citologia , Artérias Cerebrais/metabolismo , Colesterol/metabolismo , Colesterol/fisiologia , Vasos Coronários/metabolismo , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Canais de Potássio/fisiologia , Ratos , Ratos Sprague-Dawley , Vasoconstrição
7.
Int J Mol Sci ; 21(13)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32630298

RESUMO

Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17ß-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0-3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Estradiol/farmacologia , Animais , Aorta/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Colesterol/fisiologia , Modelos Animais de Doenças , Estradiol/metabolismo , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Fibrose , Lipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Tempo , Calcificação Vascular
8.
Psychol Aging ; 35(4): 508-516, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32105111

RESUMO

Previous studies suggest that cholesterol metabolic dysregulation, characterized by abnormally low or high serum total cholesterol (TC) values, constitutes a risk for pronounced cognitive decline in old age. We tested this prediction using a population-based representative Swedish sample (N = 382), born in 1901-1902, and subsequently assessed on TC and 3 cognitive outcomes (verbal ability, spatial ability, and perceptual-motor-speed) at ages 70, 75, 79, 85, 88, and 90. None of the participants were on lipid-lowering medication, as prescription availability for these medications were not initiated in Sweden until the mid-1990s. We used a 3-level hierarchical model, with cognitive tests nested within time, nested within individuals. Estimates from this model revealed a nonlinear between-person association between TC and cognition, indicating that low, and to some degree high, TC values were associated with poorer cognition. This association was stronger among nondementia-cases (n = 255). Among subsequent dementia cases (n = 127), the data suggested a linear trend, indicating that lower TC values were associated with poorer cognition. TC levels declined over time in the vast majority (96%), and the steepness of this decline was associated with the rate of cognitive decline. This within-person association was particularly strong among incident dementia cases with low TC values. Our findings indicate an optimal range of TC values associated with better cognition in old age and that the within-person association between TC and cognition is related to dementia pathologies. Further, our findings demonstrate the need to separate between-person from within-person associations when evaluating the relation between TC and cognition in old age. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Colesterol/efeitos adversos , Envelhecimento Cognitivo/fisiologia , Idoso , Idoso de 80 Anos ou mais , Colesterol/fisiologia , Feminino , Humanos , Masculino
9.
Am J Respir Cell Mol Biol ; 62(6): 709-718, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31945301

RESUMO

Chronic hypoxia (CH) augments depolarization-induced pulmonary vasoconstriction through superoxide-dependent, Rho kinase-mediated Ca2+ sensitization. Nicotinamide adenine dinucleotide phosphate oxidase and EGFR (epidermal growth factor receptor) signaling contributes to this response. Caveolin-1 regulates the activity of a variety of proteins, including EGFR and nicotinamide adenine dinucleotide phosphate oxidase, and membrane cholesterol is an important regulator of caveolin-1 protein interactions. We hypothesized that derangement of these membrane lipid domain components augments depolarization-induced Ca2+ sensitization and resultant vasoconstriction after CH. Although exposure of rats to CH (4 wk, ∼380 mm Hg) did not alter caveolin-1 expression in intrapulmonary arteries or the incidence of caveolae in arterial smooth muscle, CH markedly reduced smooth muscle membrane cholesterol content as assessed by filipin fluorescence. Effects of CH on vasoreactivity and superoxide generation were examined using pressurized, Ca2+-permeabilized, endothelium-disrupted pulmonary arteries (∼150 µm inner diameter) from CH and control rats. Depolarizing concentrations of KCl evoked greater constriction in arteries from CH rats than in those obtained from control rats, and increased superoxide production as assessed by dihydroethidium fluorescence only in arteries from CH rats. Both cholesterol supplementation and the caveolin-1 scaffolding domain peptide antennapedia-Cav prevented these effects of CH, with each treatment restoring membrane cholesterol in CH arteries to control levels. Enhanced EGF-dependent vasoconstriction after CH similarly required reduced membrane cholesterol. However, these responses to CH were not associated with changes in EGFR expression or activity, suggesting that cholesterol regulates this signaling pathway downstream of EGFR. We conclude that alterations in membrane lipid domain signaling resulting from reduced cholesterol content facilitate enhanced depolarization- and EGF-induced pulmonary vasoconstriction after CH.


Assuntos
Cálcio/fisiologia , Caveolina 1/biossíntese , Colesterol/fisiologia , Hipóxia/fisiopatologia , Lipídeos de Membrana/fisiologia , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/fisiopatologia , Vasoconstrição/fisiologia , Animais , Caveolina 1/genética , Doença Crônica , Receptores ErbB/fisiologia , Hipóxia/metabolismo , Masculino , Potenciais da Membrana , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Superóxidos/metabolismo
10.
J Neurochem ; 152(6): 663-674, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31777963

RESUMO

Synaptic strength depends on the number of cell-surface neurotransmitter receptors in dynamic equilibrium with intracellular pools. Dysregulation of this homeostatic balance occurs, for example in myasthenia gravis, an autoimmune disease characterized by a decrease in the number of postsynaptic nicotinic acetylcholine receptors (nAChRs). Monoclonal antibody mAb35 mimics this effect. Here we use STORM nanoscopy to characterize the individual and ensemble dynamics of monoclonal antibody-crosslinked receptors in the clonal cell line CHO-K1/A5, which robustly expresses adult muscle-type nAChRs. Antibody labeling of live cells results in 80% receptor immobilization. The remaining mobile fraction exhibits a heterogeneous combination of Brownian and anomalous diffusion. Single-molecule trajectories exhibit a two-state switching behavior between free Brownian walks and anticorrelated walks within confinement areas. The latter act as permeable fences (~34 nm radius, ~400 ms lifetime). Dynamic clustering, trapping, and immobilization also occur in larger nanocluster zones (120-180 nm radius) with longer lifetimes (11 ± 1 s), in a strongly cholesterol-sensitive manner. Cholesterol depletion increases the size of the clustering phenomenon; cholesterol enrichment has the opposite effect. The disclosed high proportion of monoclonal antibody-crosslinked immobile receptors, together with their anomalous, cholesterol-sensitive diffusion and clustering, provides new insights into the antibody-enhanced antigenic modulation that leads to physiopathological internalization and degradation of receptors in myasthenia.


Assuntos
Anticorpos Monoclonais/farmacologia , Colesterol/fisiologia , Receptores Nicotínicos/metabolismo , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Células CHO , Cricetulus , Reagentes para Ligações Cruzadas , Ciclodextrinas/farmacologia , Difusão , Camundongos , Miastenia Gravis/metabolismo , Receptores Nicotínicos/química
11.
Nat Rev Mol Cell Biol ; 21(4): 225-245, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31848472

RESUMO

Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.


Assuntos
Colesterol/biossíntese , Colesterol/metabolismo , Colesterol/fisiologia , Animais , Ésteres do Colesterol/metabolismo , Homeostase/fisiologia , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipoproteínas/metabolismo
12.
Biochim Biophys Acta Biomembr ; 1861(12): 183056, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31473192

RESUMO

The membrane composition modulates membrane fusion by altering membrane physical properties and the structure, organization and dynamics of fusion proteins and peptides. The journey of developing peptide-based viral fusion inhibitors is often stalled by the change in lipid composition of viral and target membranes. This makes it important to study the role of membrane composition on the organization, dynamics and fusion inhibiting abilities of the peptide-based fusion inhibitors. Cholesterol, an important constituent of mammalian cell membrane, modulates bilayer properties in multiple ways and impart its effect on the membrane fusion. We have previously shown that TG-23 peptide derived from phagosomal coat protein, coronin 1, shows significant inhibition of fusion between membranes without cholesterol. In this work, we have studied the effect of the TG-23 peptide on the polyethylene glycol-mediated membrane fusion in presence of different concentrations of membrane cholesterol. Our results show that the inhibitory effect of TG-23 is being completely reversed in cholesterol containing membranes. We have evaluated the structure, organization, dynamics and depth of penetration of TG-23 in membranes having different lipid compositions and its effect on membrane properties. Our results demonstrate that cholesterol does not affect the secondary structure of the peptide, however, alters the depth of penetration of the peptide and modifies peptide organization and dynamics. The cholesterol dependent change in organization and dynamics of the peptide influences its efficacy in membrane fusion. Therefore, we envisage that the study of peptide organization and dynamics is extremely important to determine the effect of peptide on the membrane fusion.


Assuntos
Membrana Celular/fisiologia , Colesterol/metabolismo , Proteínas dos Microfilamentos/química , Sequência de Aminoácidos , Animais , Membrana Celular/química , Colesterol/química , Colesterol/fisiologia , Humanos , Bicamadas Lipídicas/química , Metabolismo dos Lipídeos/fisiologia , Lipídeos/química , Fusão de Membrana/efeitos dos fármacos , Fusão de Membrana/fisiologia , Proteínas de Fusão de Membrana/química , Proteínas de Fusão de Membrana/metabolismo , Proteínas de Fusão de Membrana/fisiologia , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/fisiologia , Peptídeos/química , Fosfatidilcolinas/química , Polietilenoglicóis/química , Estrutura Secundária de Proteína
13.
Top Spinal Cord Inj Rehabil ; 25(3): 248-259, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31548792

RESUMO

Background: Recent studies in nondisabled individuals have demonstrated that low-volume high-intensity interval training (HIIT) can improve cardiometabolic health similar to moderate-intensity training (MIT) despite requiring 20% of the overall time commitment. To date, there have been no studies assessing the effects of HIIT for improving cardiometabolic health in individuals with SCI. Objectives: The primary purpose of this pilot study was to compare the effects of 6 weeks of low-volume HIIT vs MIT using arm crank ergometer exercise to improve body composition, cardiovascular fitness, glucose tolerance, blood lipids, and blood pressure in a cohort of individuals with longstanding SCI. Methods: Participants were randomized to 6 weeks of HIIT or MIT arm crank exercise training. Aerobic capacity, muscular strength, blood lipids, glucose tolerance, blood pressure, and body composition were assessed at baseline and 6 weeks post training. Results: Seven individuals (6 male, 1 female; n = 3 in MIT and n = 4 in HIIT; mean age 51.3 ± 10.5 years) with longstanding SCI completed the study. The preliminary findings from this pilot study demonstrated that individuals with SCI randomized to either 6 weeks of HIIT or MIT displayed improvements in (a) insulin sensitivity, (b) cardiovascular fitness, and (c) muscular strength (p < .05). However, MIT led to greater improvements in arm fat percent and chest press strength compared to HIIT (p < .05). Conclusion: No differences between MIT and HIIT were observed. Both conditions led to improvements in insulin sensitivity, aerobic capacity, muscle strength, and blood lipids in individuals with SCI. Future larger cohort studies are needed to determine if the shorter amount of time required from HIIT is preferable to current MIT exercise recommendations.


Assuntos
Aptidão Cardiorrespiratória , Treinamento Intervalado de Alta Intensidade/métodos , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/reabilitação , Adulto , Pressão Sanguínea , Composição Corporal , Colesterol/fisiologia , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Força Muscular , Consumo de Oxigênio , Projetos Piloto
15.
Cells ; 8(5)2019 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035320

RESUMO

Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol trafficking in endothelial cell signaling. Small molecule inhibitors of cholesterol trafficking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed.


Assuntos
Inibidores da Angiogênese/farmacologia , Colesterol/fisiologia , Células Endoteliais , Neoplasias , Neovascularização Patológica , Animais , Transporte Biológico/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Cell ; 176(5): 1040-1053.e17, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30712872

RESUMO

Sphingomyelin and cholesterol are essential lipids that are enriched in plasma membranes of animal cells, where they interact to regulate membrane properties and many intracellular signaling processes. Despite intense study, the interaction between these lipids in membranes is not well understood. Here, structural and biochemical analyses of ostreolysin A (OlyA), a protein that binds to membranes only when they contain both sphingomyelin and cholesterol, reveal that sphingomyelin adopts two distinct conformations in membranes when cholesterol is present. One conformation, bound by OlyA, is induced by stoichiometric, exothermic interactions with cholesterol, properties that are consistent with sphingomyelin/cholesterol complexes. In its second conformation, sphingomyelin is free from cholesterol and does not bind OlyA. A point mutation abolishes OlyA's ability to discriminate between these two conformations. In cells, levels of sphingomyelin/cholesterol complexes are held constant over a wide range of plasma membrane cholesterol concentrations, enabling precise regulation of the chemical activity of cholesterol.


Assuntos
Membrana Celular/ultraestrutura , Esfingomielinas/metabolismo , Esfingomielinas/fisiologia , Animais , Linhagem Celular , Membrana Celular/metabolismo , Colesterol/metabolismo , Colesterol/fisiologia , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/ultraestrutura , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/ultraestrutura , Humanos , Microdomínios da Membrana/metabolismo , Conformação Molecular
18.
Drug Res (Stuttg) ; 69(8): 419-427, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30776841

RESUMO

Caveolae have impressive morphological highlights of the cytomembrane of mammalian cells which involve in wide diversity of cellular functions involving signaling pathways and cholesterol hastening. Caveolin proteins possess a 'scaffolding' domain which for caveolin-1 and caveolin-3 appear to act a dominant role in signal regulation through caveolae. Caveolin-1 is treated to be protein in the cytomembrane entrapped with caveolae in endothelial cells and vascular smooth muscle cells which diminish nitric oxide (NO) by fill up the calcium/calmodulin (Ca2+/CaM) confining point of endothelial nitric oxide synthase (eNOS), decrease NO generation produce endothelial dysfunction and atherosclerotic injury development. It is a cholesterol-binding layer protein associated with cell cholesterol transport and also shows cardioprotective action through ischemic preconditioning (IPC) in diabetic and postmenopausal rat heart. Additionally it is ensnared in the procedures of tumorigenesis, prostate disease, and inflammation. The present study in the paper is to explore the structural functionalities of caveolins and their contributory role in CVS disorders and various other diseases.


Assuntos
Caveolinas/fisiologia , Adipócitos/química , Adipócitos/ultraestrutura , Doença de Alzheimer/etiologia , Animais , Doenças Cardiovasculares/etiologia , Cavéolas/química , Caveolinas/farmacologia , Caveolinas/uso terapêutico , Colesterol/fisiologia , Diabetes Mellitus Tipo 2/etiologia , Inflamação/etiologia , Insulina/fisiologia , Precondicionamento Isquêmico , Rim/fisiologia , Rim/fisiopatologia , Doenças Musculares/etiologia , Neoplasias/etiologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/fisiologia , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/fisiologia , Sistema Respiratório/citologia , Transdução de Sinais , Testosterona/deficiência , Testosterona/fisiologia , Vertebrados/anatomia & histologia
19.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(2): 128-136, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30471426

RESUMO

Cholesterol is an essential component of cell membranes, and is required for mammalian pentameric ligand-gated ion channel (pLGIC) function. Computational studies suggest direct interactions between cholesterol and pLGICs but experimental evidence identifying specific binding sites is limited. In this study, we mapped cholesterol binding to Gloeobacter ligand-gated ion channel (GLIC), a model pLGIC chosen for its high level of expression, existing crystal structure, and previous use as a prototypic pLGIC. Using two cholesterol analogue photolabeling reagents with the photoreactive moiety on opposite ends of the sterol, we identified two cholesterol binding sites: an intersubunit site between TM3 and TM1 of adjacent subunits and an intrasubunit site between TM1 and TM4. In both the inter- and intrasubunit sites, cholesterol is oriented such that the 3­OH group points toward the center of the transmembrane domains rather than toward either the cytosolic or extracellular surfaces. We then compared this binding to that of the cholesterol metabolite, allopregnanolone, a neurosteroid that allosterically modulates pLGICs. The same binding pockets were identified for allopregnanolone and cholesterol, but the binding orientation of the two ligands was markedly different, with the 3­OH group of allopregnanolone pointing to the intra- and extracellular termini of the transmembrane domains rather than to their centers. We also found that cholesterol increases, whereas allopregnanolone decreases the thermal stability of GLIC. These data indicate that cholesterol and neurosteroids bind to common hydrophobic pockets in the model pLGIC, GLIC, but that their effects depend on the orientation and specific molecular interactions unique to each sterol.


Assuntos
Colesterol/metabolismo , Canais Iônicos de Abertura Ativada por Ligante/fisiologia , Neurotransmissores/metabolismo , Sítios de Ligação/fisiologia , Membrana Celular/metabolismo , Colesterol/fisiologia , Cianobactérias/metabolismo , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Ligantes , Modelos Moleculares , Neurotransmissores/fisiologia , Marcadores de Fotoafinidade/metabolismo , Pregnanolona/metabolismo , Ligação Proteica/fisiologia , Domínios Proteicos/fisiologia
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