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1.
Alzheimers Res Ther ; 13(1): 181, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727970

RESUMO

BACKGROUND: Members of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in amyloid precursor protein (APP) processing and ß-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. We have analyzed whether ApoER2-ICD is able to regulate the expression of other LDL receptors, and we focused on LRP3, the most unknown member of this family. We analyzed LRP3 expression in middle-aged individuals (MA) and in cases with Alzheimer's disease (AD)-related pathology, and the relation of LRP3 with APP. METHODS: The effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in the presence of recombinant reelin or Aß42 peptide, were evaluated by microarray, qRT-PCRs, and western blots in SH-SY5Y cells. LRP3 expression was analyzed in human frontal cortex extracts from MA subjects (mean age 51.8±4.8 years) and AD-related pathology subjects [Braak neurofibrillary tangle stages I-II, 68.4±8.8 years; III-IV, 80.4 ± 8.8 years; V-VI, 76.5±9.7 years] by qRT-PCRs and western blot; LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Chloroquine was employed to block the lysosomal/autophagy function. RESULTS: We have identified that ApoER2 overexpression increases LRP3 expression, also after reelin stimulation of ApoER2 signaling. The same occurred following ApoER2-ICD overexpression. In extracts from subjects with AD-related pathology, the levels of LRP3 mRNA and protein were lower than those in MA subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, particularly in the membrane fraction. In cell supernatants, levels of APP fragments from the amyloidogenic (sAPPα) or non-amyloidogenic (sAPPß) pathways, as well as Aß peptides, were drastically reduced with respect to mock-transfected cells. The inhibitor of lysosomal/autophagy function, chloroquine, significantly increased full-length APP, APP-CTF, and sAPPα levels. CONCLUSIONS: ApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Proteínas Relacionadas a Receptor de LDL , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Apolipoproteínas , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Pessoa de Meia-Idade
2.
Zhongguo Gu Shang ; 34(10): 971-7, 2021 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-34726028

RESUMO

OBJECTIVE: To evaluate the effect of one-stage treatment of bone morphogenetic protein 2 combined with Jifusheng in the experimental model of osteomyelitis in rabbits. METHODS: The model of chronic osteomyelitis of tibia was established in 30 3-month-old male New Zealand white rabbits with a body weight of (2.0±0.5) kg, and the model was verified 4 weeks after operation. Thirty rabbits with osteomyelitis were randomly divided into 3 groups with 10 rabbits in each group (n= 10). The model group did not do any treatment after focal debridement, treatment group A was implanted with musculosheng at the site of focal debridement and bone defect, and treatment group B was implanted with apolipoprotein 2-Jifusheng at the site of focal debridement and bone defect. The therapeuticeffect was evaluated by blood biochemical, microbiological, imaging, pathological and immunohistochemical examination 8 weeks after operation. RESULTS: At 4 weeks after operation, 30 rabbits with osteomyelitis were successfully validated. The results of serological examination showed that the hypersensitive C-reactive protein (CRP) and white blood cell count(WBC)in the model group were significantly higher than those in the blank group at 2 and 4 weeks after operation. Eight weeks after treatment, the detection of blood indexes showed that the white blood cell count (WBC)and hypersensitive C reactive protein (CRP)in treatment group A and treatment group B were significantly lower than those in the model group (P<0.05), but there was no significant difference between treatment group An and treatment group B (P>0.05). Eight weeks after treatment, the bone defect area was measured. The bone volume/total volume (BV/TV) and bone mineral density (BMD)in treatment group A and B were significantly higher than those in the model group (P<0.05), and the bone volume/total volume (BV/TV) and bone mineral density(BMD)in treatment group B were significantly higher than those in treatment group A (P<0.05), the repair of bone defect was almost complete, and the bone volume and bone mineral density increased significantly. At 8 weeks after treatment, the number of osteoblasts/bone tissue area (N.Ob/T.Ar) and the number of osteoblasts/bone tissue perimeter (N.Ob/B.Pm) in treatment group A and B were significantly higher than those in model group, and the N.Ob/T.Ar and N.Ob/B.Pm in treatment group B were significantly higher than those in treatment group A. The immunohistochemical staining of TNF- α and IL-6 around bone tissue in treatment group A and treatment group B was significantly less than that in model group, but there was no significant difference between treatment group B and treatment group A. CONCLUSION: The combined application of apolipoprotein 2-Jifusheng can promote bone repair and reduce the inflammation of the focus. it can treat rabbits with osteomyelitis in one stage, provide objective basis for the formulation of clinical treatment strategy of osteomyelitis and further promote clinical research.


Assuntos
Osteomielite , Animais , Apolipoproteínas , Densidade Óssea , Osso e Ossos , Masculino , Osteomielite/tratamento farmacológico , Coelhos , Tíbia
3.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638860

RESUMO

(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Lipoproteínas/metabolismo , Sepse/metabolismo , Apolipoproteínas/metabolismo , Aterosclerose/complicações , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Progressão da Doença , Humanos , Sepse/complicações , Triglicerídeos/metabolismo
4.
Atherosclerosis ; 334: 76-84, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34482091

RESUMO

Apolipoprotein M (apoM) is a member of the lipocalin superfamily and is predominantly associated with high-density lipoprotein (HDL). It was found that apoM is the chaperon to the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Several studies have since contributed to expand the knowledge on apoM, S1P, and the apoM/S1P-complex in cardiovascular diseases. For instance, the HDL-bound apoM/S1P complex serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. Evidence indicates, however, that the apoM/S1P complex may has both protective and harmful effects on the cardiovascular system, which suggests the need for more research to understand the interplay between these molecules. This review aims to shed light on the most recent findings on apoM/S1P-signaling and its impact on endothelial dysfunction, inflammation, and cardiovascular diseases. Finally, it will be discussed whether drugs that target apoM and/or S1P-signaling may be beneficial to patients with cardiovascular and inflammatory diseases.


Assuntos
Sistema Cardiovascular , Células Endoteliais , Apolipoproteínas/metabolismo , Apolipoproteínas M , Sistema Cardiovascular/metabolismo , Células Endoteliais/metabolismo , Humanos , Inflamação , Lisofosfolipídeos , Esfingosina
5.
Atherosclerosis ; 333: 9-15, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418683

RESUMO

BACKGROUND AND AIMS: Little is known about the long-term impact of apolipoprotein E (apoE) on residual cardiovascular risk in patients with chronic coronary syndrome (CCS) receiving statin treatment. METHODS: A total of 1109 consecutive patients (mean age, 67 ± 10 years; 83% men) with CCS who underwent their first intervention between 2000 and 2016 were included in this study. All patients had achieved low-density lipoprotein cholesterol (LDL-C) <100 mg/dL on statin treatment and were divided into two groups based on median serum apoE values. We evaluated the incidence of major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal acute coronary syndrome, and target vessel revascularization. RESULTS: A total of 552 and 557 patients were categorized to the higher and lower apoE groups, respectively. There were significant relationships between apoE levels and total cholesterol levels, triglyceride levels, high-density lipoprotein cholesterol levels, and estimated remnant cholesterol, except for LDL-C levels. During the median follow-up period of 5.1 years, 195 patients (17.6%) developed MACEs. Kaplan-Meier analysis revealed that the cumulative incidence of MACEs in the higher apoE group was significantly higher than in the lower apoE group (29.5% vs.23.8% log-rank test, p = 0.019). Using multivariable Cox hazard analysis, serum apoE level (1-mg/dL increase) (hazard ratio 1.15; 95% confidence interval 1.03-1.29, p = 0.013) was the strongest independent predictor of MACEs. CONCLUSIONS: Serum apoE level could be a strong predictor of residual cardiovascular risk in patients with CCS long-term, even if LDL-C levels are controlled with statin treatment.


Assuntos
Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Intervenção Coronária Percutânea , Idoso , Apolipoproteínas , Doenças Cardiovasculares/diagnóstico , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco
6.
Theriogenology ; 174: 9-19, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34416563

RESUMO

The circadian clock system plays an important role in regulating testosterone synthesis in mammals. Male Bmal1-/- mice are infertile with low serum testosterone levels and decreased expression of testicular steroidogenic genes, suggesting that circadian clock genes regulate testosterone biosynthesis by activating steroidogenic gene transcription. However, whether the circadian clock regulates testosterone production via other genes remains unknown. Using Bmal1-/- mice and their wild-type (WT) siblings, we aimed to identify additional genes by which the circadian clock regulates testosterone synthesis. WT and Bmal1-/- mouse testes sections had similar normal morphologies, although there was a decrease in testicular spermatozoa in the Bmal1-/- mice. Low serum testosterone levels were detected in the Bmal1-/- mice. RNA sequencing identified 37 and 48 genes that were differentially expressed between WT and Bmal1-/- mouse testes at circadian time (CT2 and CT14), respectively. The cholesterol metabolism pathway was significantly enriched in the KEGG pathway analysis, and there was lower expression of three apolipoprotein genes (Apoa1, Apoa2, and Apoc3) at CT2 in the testes of Bmal1-/- mice than in those of WT mice. These decreases in Apoa1, Apoa2, and Apoc3 expression were verified by quantitative polymerase chain reaction analysis, which also revealed downregulation of the expression of the circadian clock (Per2, Dbp, and Nr1d1) and steroidogenic (StAR, Cyp11a1, and Hsd17b3) genes. The expression of circadian clock genes was relatively stable in WT mice over a 20-h period, whereas there was clear circadian rhythmic expression of Apoa1, Apoa2, Apoc3, StAR, Cyp11a1, Hsd3b2, and Hsd17b3. Bmal1-/- mice showed severely reduced expression of testicular circadian clock genes at three time points (CT4, CT12, and CT20), and a reduction in mRNA expression levels of Apo (Apoa1, Apoa2, and Apoc3) and steroidogenic (StAR, Cyp11a1, Hsd3b2, and Hsd17b3) genes. Oil Red O staining showed decreased lipid aggregation in the Leydig cells of Bmal1-/- mouse testes. Considering the vital role of Apo genes in high-density lipoprotein formation and cholesterol transport, the present data suggest that the circadian clock system regulates testosterone production by orchestrating the rhythmic expression of Apo genes. These data extend our understanding of the role of the circadian clock in regulating testosterone production in mammals.


Assuntos
Relógios Circadianos , Testosterona , Animais , Apolipoproteínas , Proteínas CLOCK/genética , Ritmo Circadiano , Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Testículo
7.
Analyst ; 146(17): 5245-5254, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34296726

RESUMO

The affinity between functional nanoparticles (NPs) and proteins could determine the efficacy of nanoprobes, nanosensors, nanocarriers, and many other devices for biomedical applications. Therefore, it is necessary to develop analytical strategies to accurately evaluate the magnitude of these protein corona interactions in physiological media. In this work, different electrokinetic strategies were implemented to accurately determine the interactions between PEGylated ZnGa1.995Cr0.005O4 persistent luminescent NPs (ZGO-PEG) and two important serum proteins: human serum albumin (HSA), the most abundant serum protein, and apolipoprotein-E (ApoE), associated with the active transport of NPs through the blood-brain barrier. Firstly, the injection of ZGO-PEG in a background electrolyte (BGE) containing individual proteins allowed an affinity study to separately characterize each NP-protein system. Then, the same procedure was applied in a buffer containing a mixture of the two proteins at different molar ratios. Finally, the NPs were pre-incubated with one protein and thereafter electrokinetically separated in a BGE containing the second protein. These analytical strategies revealed the mechanisms (comparative, cooperative or competitive systems) and the magnitude of their interactions, resulting in all cases in notably higher affinity and stability between ZGO-PEG and ApoE (Ka = 1.96 ± 0.25 × 1010 M-M) compared to HSA (Ka = 4.60 ± 0.41 × 106 M-M). For the first time, the inter-protein ApoE/HSA interactions with ZGO-PEG were also demonstrated, highlighting the formation of a ternary ZGO-PEG/ApoE/HSA nanocomplex. These results open the way for a deeper understanding of the protein corona formation, and the development of versatile optical imaging applications for ZGO-PEG and other systemically delivered nanoprobes ideally vectorized to the brain.


Assuntos
Nanopartículas , Coroa de Proteína , Albuminas , Apolipoproteínas , Apolipoproteínas E , Humanos , Luminescência
8.
J Invertebr Pathol ; 184: 107647, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34303711

RESUMO

Insect Apolipophorin-III is a multifunctional protein and also plays an important role in insect innate immunity. Early transcriptome and proteome studies indicated that the gene expression level of Bombyx mori Apolipophorin-III (BmApoLp-III) in silkworm larvae infected with Beauveria bassiana was significantly up-regulated. In this study, BmApoLp-III gene was cloned, its expression patterns in different larval tissues investigated, the BmApoLp-III protein was successfully expressed with prokaryotic expression system and its antifungal effect was verified. The results showed that the BmApoLp-III gene was expressed in all the tested tissues of the 5th instar larvae infected by B. bassiana, with the highest expression in fat body. The fungistatic zone test showed that the recombinant BmApoLp-III has a significant antifungal effect on B. bassiana. Injecting purified BmApoLp-III to the larvae delayed the onset and death of the infected larvae. Conversely, silencing BmApoLp-III gene by RNAi resulted in early morbidity and death of the infected larvae. At the same time, injecting BmApoLp-III up-regulated the expression of genes including BmßGRP4 and BmMyd88 in the Toll signaling pathway, BmCTL5 and BmHOP in the Jak/STAT signaling pathway, serine proteinase inhibitor BmSerpin5, and antimicrobial peptide BmCecA, but down-regulated the expression of BmTak1 of Imd signaling pathway; while silencing BmApoLp-III gene down-regulated the expression of BmßGRP1 and BmSpaetzle, BmCTL5 and BmHOP, BmSerpin2 and BmSerpin5, BmBAEE and BmPPO2 of relevant pathways and BmCecA, but up-regulated the expression of BmPGRP-Lc and BmTak1 of Imd pathway. These results indicate that the BmApoLp-III could not only directly inhibit B. bassiana, but also participate in regulation of the expression of immune signaling pathway related genes, promote the expression of immune effectors, and indirectly inhibit the reproduction of B. bassiana in the silkworm.


Assuntos
Apolipoproteínas/genética , Beauveria/fisiologia , Bombyx/genética , Interações Hospedeiro-Patógeno , Imunidade Inata/genética , Proteínas de Insetos/genética , Regulação para Cima/imunologia , Animais , Apolipoproteínas/metabolismo , Bombyx/crescimento & desenvolvimento , Bombyx/imunologia , Bombyx/microbiologia , Regulação Fúngica da Expressão Gênica , Proteínas de Insetos/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/imunologia , Larva/microbiologia , Transdução de Sinais
11.
Kidney Int ; 100(1): 19-21, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34154709

RESUMO

Apolipoprotein L1 (APOL1) high-risk genotypes strongly associate with HIV-associated nephropathy, and antiretroviral therapy reduces the incidence of HIV-associated nephropathy and progression to end-stage kidney disease. Wudil et al. report cross-sectional APOL1 associations with proteinuria and estimated glomerular filtration rate in a northern Nigerian sample with HIV infection on antiretroviral therapy. Multiple ethnic groups with different APOL1 risk variant frequencies were included. Overall, APOL1 was associated with proteinuric chronic kidney disease; however, relationships with underlying causes of nephropathy and progression rates require further study.


Assuntos
Apolipoproteína L1 , Infecções por HIV , Adulto , Apolipoproteína L1/genética , Apolipoproteínas/genética , Estudos Transversais , Genótipo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Rim , Lipoproteínas HDL/genética , Nigéria , Fenótipo
12.
Arch Insect Biochem Physiol ; 107(3): e21823, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34075635

RESUMO

The 30 K proteins are the major silkworm hemolymph proteins and are involved in a variety of physiological processes, such as nutrient and energy storage, embryogenesis, immune response, and inhibition of apoptosis. The Bm30K-15 protein is one of the 30 K proteins and is abundant in the hemolymph of fifth instar silkworm larva. We previously found that the Bm30K-15 protein can be acetylated. In the present study, we found that acetylation can improve the protein stability of Bm30K-15. Further exploration confirmed that the increase in protein stability by acetylation was caused by competition between acetylation and ubiquitination. In summary, these findings aim to provide insight into the effect of acetylation modification on the protein level and stability of the Bm30K-15 and the possible molecular mechanism of its existence in silkworm, Bombyx mori.


Assuntos
Apolipoproteínas/metabolismo , Bombyx/metabolismo , Proteínas de Insetos/metabolismo , Acetilação , Animais , Estabilidade Proteica , Ubiquitinação , Regulação para Cima
13.
Sci Rep ; 11(1): 13151, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162950

RESUMO

Several factors influence an individual's susceptibility in inter-individual lipid changes and its role in the onset of type-2 diabetes mellitus (T2DM). Considering the above fact, the present investigation focuses on determining the association between fatty acid desaturase 2 (FADS2) rs174575 (C/G) polymorphism, circulating lipid levels and susceptibility to type-2 diabetes mellitus. As per the inclusion and exclusion criteria a total of 429 subjects (non-diabetic-216; diabetic-213) were recruited for the study. Glycemic and lipid profile status were assessed using commercially available kits. Based on the previous reports SNP rs174575 of fatty acid desaturase gene (FADS2) was selected and identified using the dbSNP database. The amplified products were sequenced by means of Sanger sequencing method. Lipid profile status and apolipoprotein levels revealed statistically significant difference between the groups. Three models were assessed namely, recessive model (CC vs CG + GG), dominant model (CC + CG vs GG) and additive model (CC vs CG vs GG). The recessive model, displayed a statistically significant variations between the circulating lipid levels in T2DM. The multivariate model with genotype (G allele carriers), triglyceride (TG) and insulin served as a predictive model. The study results potentiate the functional link between FADS2 gene polymorphism, lipid levels and type-2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Ácidos Graxos Dessaturases/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Adulto , Apolipoproteínas/sangue , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Dislipidemias/sangue , Dislipidemias/enzimologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Triglicerídeos/sangue
14.
West Afr J Med ; 38(6): 511-519, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174036

RESUMO

BACKGROUND: The Apolipoprotein 1 (APOL1) protein is a product of the human APOL1 gene located on chromosome 22q13.1 and performs functions including lipid transport and metabolism, programmed cell death, autophagy and innate immunity against intracellular pathogens. It is unique among its gene family in its possession of a signal peptide that confers on it the ability for export out of the cell and into the blood stream. The aim of this review is to explore the genetic epidemiology and biology of the APOL1 gene, describe its association with different renal and extra-renal disorders and highlight the timelines of the discoveries of the various associations. METHODS: A literature search was carried out using combination of terms including "apolipoproteins", "apolipoprotein L", "APOL1", "genetics of APOL1", "Chronic Kidney Disease (CKD) and APOL1"," APOL1 and associated diseases" covering the period January 1990 to April 2020. RESULTS: High frequency of the APOL1 gene arose as a result of natural selection in East and West Africa, regions endemic for Trypanosoma brucei infection. High frequencies are also reported among individuals of African ancestry in North America. APOL1 G1 and G2 variants protect against Trypanosoma brucei rhodesiense having overcome their virulence through the serum trypanolytic factor. Although protective against infection from trypanosomes, these alleles have also been shown to increase the risk of several disorders including various forms of chronic kidney diseases, schizophrenia, stroke, cancer, and pre - eclampsia. CONCLUSION: The elucidation of the APOL1 gene has deepened understanding of racial disparities in health and disease. Growing understanding of the genetics and functions of APOL1 has potential to enhance translational benefits for development of new biomarkers, preventive and therapeutic interventions in the context of precision medicine.


Assuntos
Apolipoproteína L1 , Lipoproteínas HDL , África Ocidental , Apolipoproteínas/genética , Humanos , Lipoproteínas HDL/genética , Epidemiologia Molecular
15.
Nutrients ; 13(5)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067585

RESUMO

We previously observed beneficial effects of a carbohydrate-reduced, high-protein (CRHP) diet on cardiovascular risk markers in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, when all food was provided to subjects as ready-to-eat meals. Here, we report the results from a 6-month open label extension: 28 patients with T2DM were instructed to self-prepare the CRHP diet with dietetic guidance. At weeks 0, 6, 12, and 36, fasting and postprandial (4-h meal test) blood samples were collected for measurements of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triacylglycerol (TG), apolipoproteins A1 and B, non-esterified fatty acids (NEFA), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6. Diurnal blood pressure and heart rate were also assessed. At the end of the study (week 36), concentrations of fasting total and LDL-cholesterol, fasting and postprandial NEFA and TG, and fasting apolipoprotein-B, CRP and TNF-α concentrations were significantly lower compared with week 0 (p < 0.05). A significant decrease in diurnal heart rate was also observed. From week 12 to 36, an increase in HDL-cholesterol and apolipoprotein-A1 concentrations and a further reduction in fasting and postprandial NEFA (p < 0.05) were found. These changes were independent of minor fluctuations in body weight. We conclude that the substitution of dietary carbohydrate for protein and fat has beneficial effects on several cardiovascular risk markers in patients with T2DM, which are maintained or augmented over the next 6 months when patients select and prepare the CRHP diet on their own in a dietitian-supported setting.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Dieta Rica em Proteínas e Pobre em Carboidratos/métodos , Preferências Alimentares/psicologia , Idoso , Apolipoproteínas/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Culinária , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Dieta Rica em Proteínas e Pobre em Carboidratos/psicologia , Jejum/sangue , Ácidos Graxos não Esterificados/sangue , Feminino , Seguimentos , Fatores de Risco de Doenças Cardíacas , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Estudos Prospectivos , Triglicerídeos/sangue
16.
J Phys Chem B ; 125(18): 4746-4756, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33939404

RESUMO

Protein-lipid interactions govern the structure and function of lipoprotein particles, which transport neutral lipids and other hydrophobic cargo through the blood stream. Apolipoproteins cover the surface of lipoprotein particles, including low-density (LDL) and high-density (HDL) lipoproteins, and determine their function. Previous work has focused on small peptides derived from these apolipoproteins or used such artificial lipid systems as Langmuir monolayers or the lipid disc assay to determine how apolipoproteins interact with the neutral lipid interface. Here, we focus on a recurring protein domain found in many neutral lipid-binding proteins, the amphipathic α-helix bundle. We use liquid droplet tensiometry to investigate protein-lipid interactions on an oil droplet, which mimics the real lipoprotein interface. The N-terminus of apoE 3 and full-length apoLp-III serve as model proteins. We find that each protein interacts with lipid monolayers at the oil-aqueous interface in unique ways. For the first time, we show that helix bundle unfolding is critical for proper protein insertion into the lipid monolayer at the oil-aqueous interface and that specific membrane lipids promote the rebinding of protein upon fluctuation in droplet size. These results shed new light on how amphipathic apolipoprotein α-helix bundles interact with neutral lipid particles.


Assuntos
Apolipoproteínas , Lipoproteínas , Apolipoproteína E3 , Apolipoproteínas/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice
17.
Clin Nutr ; 40(5): 2556-2575, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33933722

RESUMO

BACKGROUND & AIMS: Marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower circulating levels of triacylglycerols (TAGs), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) may reduce cholesterol levels. Clinical studies on effects of these dietary or supplemental PUFAs on other blood fat fractions are few and have shown conflicting results. This study aimed to determine effects of high-dose supplemental n-3 (EPA + DHA) and n-6 (LA) PUFAs from high-quality oils on circulating lipoprotein subfractions and standard lipids (primary outcomes), as well as apolipoproteins, fatty acids, and glycemic control (secondary outcomes), in females and males with abdominal obesity. METHODS: This was a randomized double-blind crossover study with two 7-wk intervention periods separated by a 9-wk washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (TAG fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we investigated lipoprotein particle subclasses by nuclear magnetic resonance spectroscopy, as well as standard lipids, apolipoproteins, fatty acid profiles, and glucose and insulin. Data were analyzed by linear mixed-effects modeling with 'subjects' as the random factor. RESULTS: The difference between interventions in relative change scores was among the lipoprotein subfractions significant for total very-low-density lipoproteins (VLDLs) (n-3 vs. n-6: -38%∗ vs. +16%, p < 0.001; ∗: significant within-treatment change score), large VLDLs (-58%∗ vs. -0.91%, p < 0.001), small VLDLs (-57%∗ vs. +41%∗, p < 0.001), total low-density lipoproteins (LDLs) (+5.8%∗ vs. -4.3%∗, p = 0.002), large LDLs (+23%∗ vs. -2.1%, p = 0.004), total high-density lipoproteins (HDLs) (-6.0%∗ vs. +3.7%, p < 0.001), large HDLs (+11%∗ vs. -5.3%, p = 0.001), medium HDLs (-24%∗ vs. +6.2%, p = 0.030), and small HDLs (-9.9%∗ vs. +9.6%∗, p = 0.002), and among standard lipids for TAGs (-16%∗ vs. -2.6%, p = 0.014), non-esterified fatty acids (-19%∗ vs. +5.5%, p = 0.033), and total cholesterol (-0.28% vs. -4.4%∗, p = 0.042). A differential response in relative change scores was also found for apolipoprotein (apo)B (+0.40% vs. -6.0%∗, p = 0.008), apoA-II (-6.0%∗ vs. +1.5%, p = 0.001), apoC-II (-11%∗ vs. -1.7%, p = 0.025), and apoE (+3.3% vs. -3.8%, p = 0.028). CONCLUSIONS: High-dose supplementation of high-quality oils with n-3 (EPA + DHA) or n-6 (LA) PUFAs was followed by reductions in primarily TAG- or cholesterol-related markers, respectively. The responses after both interventions point to changes in the lipoprotein-lipid-apolipoprotein profile that have been associated with reduced cardiometabolic risk, also among people with TAG or LDL-C levels within the normal range. REGISTRATION: Registered under ClinicalTrials.gov Identifier: NCT02647333. CLINICAL TRIAL REGISTRATION: Registered at https://clinicaltrials.gov/ct2/show/NCT02647333.


Assuntos
Apolipoproteínas/sangue , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-6/administração & dosagem , Lipídeos/sangue , Lipoproteínas/classificação , Biomarcadores/sangue , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal
18.
mBio ; 12(3)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006657

RESUMO

The Agrobacterium growth pole ring (GPR) protein forms a hexameric ring at the growth pole (GP) that is essential for polar growth. GPR is large (2,115 amino acids) and contains 1,700 amino acids of continuous α-helices. To dissect potential GPR functional domains, we created deletions of regions with similarity to human apolipoprotein A-IV (396 amino acids), itself composed of α-helical domains. We also tested deletions of the GPR C terminus. Deletions were inducibly expressed as green fluorescent protein (GFP) fusion proteins and tested for merodiploid interference with wild-type (WT) GPR function, for partial function in cells lacking GPR, and for formation of paired fluorescent foci (indicative of hexameric rings) at the GP. Deletion of domains similar to human apolipoprotein A-IV in GPR caused defects in cell morphology when expressed in trans to WT GPR and provided only partial complementation to cells lacking GPR. Agrobacterium-specific domains A-IV-1 and A-IV-4 contain predicted coiled coil (CC) regions of 21 amino acids; deletion of CC regions produced severe defects in cell morphology in the interference assay. Mutants that produced the most severe effects on cell shape also failed to form paired polar foci. Modeling of A-IV-1 and A-IV-4 reveals significant similarity to the solved structure of human apolipoprotein A-IV. GPR C-terminal deletions profoundly blocked complementation. Finally, peptidoglycan (PG) synthesis is abnormally localized circumferentially in cells lacking GPR. The results support the hypothesis that GPR plays essential roles as an organizing center for membrane and PG synthesis during polar growth.IMPORTANCE Bacterial growth and division are extensively studied in model systems (Escherichia coli, Bacillus subtilis, and Caulobacter crescentus) that grow by dispersed insertion of new cell wall material along the length of the cell. An alternative growth mode-polar growth-is used by some Actinomycetales and Proteobacteria species. The latter phylum includes the family Rhizobiaceae, in which many species, including Agrobacterium tumefaciens, exhibit polar growth. Current research aims to identify growth pole (GP) factors. The Agrobacterium growth pole ring (GPR) protein is essential for polar growth and forms a striking hexameric ring structure at the GP. GPR is long (2,115 amino acids), and little is known about regions essential for structure or function. Genetic analyses demonstrate that the C terminus of GPR, and two internal regions with homology to human apolipoproteins (that sequester lipids), are essential for GPR function and localization to the GP. We hypothesize that GPR is an organizing center for membrane and cell wall synthesis during polar growth.


Assuntos
Agrobacterium tumefaciens/genética , Apolipoproteínas/genética , Proteínas de Ciclo Celular/genética , Polaridade Celular/genética , Parede Celular/metabolismo , Agrobacterium tumefaciens/química , Agrobacterium tumefaciens/crescimento & desenvolvimento , Apolipoproteínas/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Divisão Celular , Proteínas de Fluorescência Verde
19.
Cells ; 10(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918571

RESUMO

Epidemiological studies have established that a high plasma high density lipoprotein cholesterol (HDL-C) level is associated with reduced cardiovascular risk. However, recent randomised clinical trials of interventions that increase HDL-C levels have failed to establish a causal basis for this relationship. This has led to a shift in HDL research efforts towards developing strategies that improve the cardioprotective functions of HDLs, rather than simply increasing HDL-C levels. These efforts are also leading to the discovery of novel HDL functions that are unrelated to cardiovascular disease. One of the most recently identified functions of HDLs is their potent antidiabetic properties. The antidiabetic functions of HDLs, and recent key advances in this area are the subject of this review. Given that all forms of diabetes are increasing at an alarming rate globally, there is a clear unmet need to identify and develop new approaches that will complement existing therapies and reduce disease progression as well as reverse established disease. Exploration of a potential role for HDLs and their constituent lipids and apolipoproteins in this area is clearly warranted. This review highlights focus areas that have yet to be investigated and potential strategies for exploiting the antidiabetic functions of HDLs.


Assuntos
Diabetes Mellitus/sangue , Lipoproteínas HDL/sangue , Animais , Apolipoproteínas/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Estresse do Retículo Endoplasmático , Humanos , Estresse Oxidativo
20.
Nat Commun ; 12(1): 2408, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893307

RESUMO

Lipid shuttling between neurons and glia contributes to the development, function, and stress responses of the nervous system. To understand how a neuron acquires its lipid supply from specific lipoproteins and their receptors, we perform combined genetic, transcriptome, and biochemical analyses in the developing Drosophila larval brain. Here we report, the astrocyte-derived secreted lipocalin Glial Lazarillo (GLaz), a homolog of human Apolipoprotein D (APOD), and its neuronal receptor, the brain-specific short isoforms of Drosophila lipophorin receptor 1 (LpR1-short), cooperatively mediate neuron-glia lipid shuttling and support dendrite morphogenesis. The isoform specificity of LpR1 defines its distribution, binding partners, and ability to support proper dendrite growth and synaptic connectivity. By demonstrating physical and functional interactions between GLaz/APOD and LpR1, we elucidate molecular pathways mediating lipid trafficking in the fly brain, and provide in vivo evidence indicating isoform-specific expression of lipoprotein receptors as a key mechanism for regulating cell-type specific lipid recruitment.


Assuntos
Apolipoproteínas/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Animais Geneticamente Modificados , Apolipoproteínas/genética , Transporte Biológico , Encéfalo/citologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Perfilação da Expressão Gênica , Humanos , Larva/genética , Larva/metabolismo , Lipocalinas/genética , Lipocalinas/metabolismo , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/genética
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