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1.
FASEB J ; 35(9): e21814, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369624

RESUMO

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mitocôndrias/genética , Chaperonas Moleculares/genética , Monoéster Fosfórico Hidrolases/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Proteína Supressora de Tumor p53/genética , Adaptação Biológica/genética , Apoptose/genética , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glucose/genética , Células Hep G2 , Homeostase/genética , Humanos , Potencial da Membrana Mitocondrial/genética , Estresse Fisiológico/genética , Ativação Transcricional/genética
2.
BMJ Case Rep ; 14(4)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858896

RESUMO

We report a case of 34-year-old clinically asymptomatic woman who had been followed for 6 years for hyperthyroidism with thyroid stimulating hormone <0.006 uIU/mL, free T4 1.98 ng/mL, free T3 5.3 pg/mL, elevated thyroid stimulating immunoglobulin 1.70 IU/L, thyroid peroxidase antibody 38 IU/mL and thyroglobulin antibody 9.3 IU/mL. Radioiodine thyroid scan showed minimal uptake in both thyroid lobes (24-hour uptake was 0.3%). She subsequently underwent evaluation for lower abdominal pain and menstrual irregularities, which revealed a large left ovarian cyst measuring 15.9 cm × 10.8 cm × 13.2 cm and right-sided ovarian cyst measuring 2.7 cm × 3.3 cm × 3.5 cm. Laparoscopic bilateral ovarian cystectomy was performed and the final pathology revealed struma ovarii of the left ovarian cyst with the entire ovarian tumour made up of benign thyroid tissue. Thyroid function tests performed 3 months after surgical removal of struma ovarii showed euthyroidism. We present a rare case with detailed laboratory and immunological data before and after ovarian extirpation with resolution of hyperthyroidism associated with functional struma ovarii.


Assuntos
Hipertireoidismo , Neoplasias Ovarianas , Estruma Ovariano , Adulto , Feminino , Humanos , Hipertireoidismo/cirurgia , Radioisótopos do Iodo , Estruma Ovariano/cirurgia , Tomografia Computadorizada por Raios X
3.
J Am Heart Assoc ; 10(7): e019365, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33759548

RESUMO

Background Diabetic kidney disease is associated with glomerulosclerosis and poor renal perfusion. Increased capillary formation and improved perfusion may help to halt or reverse the injury. Transplanting apoptosis-resistant p53-silenced endothelial progenitor cells (p53sh-EPCs) may help improve vascularization and renal perfusion and could be more beneficial than another stem cell such as the mouse mesenchymal stromal cell (mMSC). Methods and Results Hyperglycemia and proteinuria were confirmed at 8 to 10 weeks in streptozotocin-induced type1 diabetic C57Bl/6 mice, followed by transplantation of 0.3 million p53sh-EPCs, Null-EPCs (control), or mMSC under each kidney capsule. Urine was collected weekly for creatinine and protein levels. Blood pressure was measured by direct arterial cannulation and renal perfusion was measured by renal ultrasound. The kidneys were harvested for histology and mRNA expression. Reduction of protein/creatinine (AUC) was observed in p53sh-EPC-transplanted mice more than null-EPC (1.8-fold, P=0.03) or null-mMSC (1.6-fold, P=0.04, n=4) transplanted mice. Markers for angiogenesis, such as endothelial nitric oxide synthase (1.7-fold, P=0.06), were upregulated post p53sh-EPC transplantation compared with null EPC. However, vascular endothelial growth factor-A expression was reduced (7-fold, P=0.0004) in mMSC-transplanted mice, compared with p53sh-EPC-transplanted mice. Isolectin-B4 staining of kidney section showed improvement of glomerular sclerosis when p53sh-EPC was transplanted, compared with null-EPC or mMSC. In addition, mean and peak renal blood velocity (1.3-fold, P=0.01, 1.4-fold, P=0.001, respectively) were increased in p53sh-EPC-transplanted mice, relative to null-EPC transplanted mice. Conclusions Apoptosis-resistant p53sh EPC transplantation could be beneficial in the treatment of diabetic kidney disease by decreasing proteinuria, and improving renal perfusion and glomerular architecture.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas/cirurgia , Células Progenitoras Endoteliais/transplante , Taxa de Filtração Glomerular/fisiologia , Animais , Apoptose , Nefropatias Diabéticas/fisiopatologia , Células Progenitoras Endoteliais/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
J Phys Chem B ; 125(10): 2754-2760, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33667334

RESUMO

The kinetic and calorimetric fragility indices m of binary As-Se and Se-Te chalcogenide liquids with a wide range of fragility are determined using a combination of parallel plate rheometry, beam bending viscometry, and conventional differential scanning calorimetry (DSC). It is shown that both sets of measurements lead to consistent m values only if the validity of the assumptions often implicit in the methodology for the estimation of m are considered. These assumptions are (i) the glass transition temperature Tg corresponds to a viscosity of ∼1012 Pa s and (ii) enthalpy and shear relaxation time scales τen and τshear are comparable near Tg. Both assumptions are shown to be untenable for highly fragile liquids, for which modulated DSC studies demonstrate that τen ≫ τshear near Tg. In these cases, the above-mentioned assumptions are shown to lead to consistently higher values for the kinetic fragility compared to its calorimetric counterpart.

5.
Cardiovasc Diabetol ; 20(1): 44, 2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33581737

RESUMO

BACKGROUND: Endothelial progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Effect of sodium glucose channel inhibitors (SGLT2i) such as Canagliflozin (CG) on a cellular biomarker such as CD34+ve progenitor cells, which may help predict CVD risk, in patients with T2DM with established CKD has not been explored. METHODS: This is a pilot study where 29 subjects taking metformin and/or Insulin were enrolled in a 16 week, double blind, randomized placebo matched trial, with a low dose 100 mg CG as the intervention group compared to matched placebo. Type 2 diabetes subjects (30-70 years old), with hemoglobin A1c (HbA1c) of 7-10%, were enrolled. CD34+ve cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, serum biochemistry pertaining to cardio-metabolic health, resting energy expenditure and body composition were measured. Data were collected at week 0, 8 and 16. A mixed model regression analysis was done and p value less than 0.05 was considered statistically significant. RESULTS: A significant expression of CXCR4 receptor with a concomittant increase in migratory function of CD34+ve cells was observed in CG treated group as compared to placebo group. Gene expression analysis of CD34+ve cells showed an increase in expression of antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and notable endothelial markers (PECAM1, VEGF-A, and NOS3). A significant reduction in glucose and HbA1c levels were observed along with improved systolic and diastolic blood pressure in the CG group. A significant increase in adiponectin (p = 0.006) was also noted in treatment group. Urinary exosomal protein leak in urine, examining podocyte health (podocalyxin, Wilm's tumor and nephrin) showed reduction with CG CONCLUSION: Low dose Canagliflozin has a beneficial effect on CD34+ cell function, serum biochemistry and urinary podocyte specific exosomes in type 2 diabetes.


Assuntos
Antígenos CD34/metabolismo , Glicemia/efeitos dos fármacos , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Canagliflozina/efeitos adversos , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
6.
Cell Death Dis ; 11(12): 1073, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323928

RESUMO

The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.


Assuntos
Oncogenes , Proteínas Supressoras de Tumor/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genoma Humano , Histona Desmetilases/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
7.
Inorg Chem ; 59(23): 16905-16912, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33166128

RESUMO

We present a computational study of the magnetic and electronic transport properties of cumulene-based monocobaltocene and dicobaltocene complexes. We show that the odd cumulene-based dicobaltocene complexes are a potential candidate for the ferromagnetic material. The calculation of the zero-field splitting (ZFS) parameter D confirms that the odd cumulene-based dicobaltocene complexes can be used as potential single-molecule magnets. The monocobaltocene-based complexes are found to be a good spin filter, as demonstrated by the calculation of the transmission and current versus voltage curve. The orthogonal SOMOs of the dicobaltocene complexes make them weak or a nonspin filter despite having a high spin ground state.

8.
Acc Chem Res ; 53(12): 2869-2878, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33186005

RESUMO

Core principles of chemistry are ubiquitously invoked to shed light on the nature of molecular level interactions in nanoconfined fluids, which play a pivotal role in a wide range of processes in geochemistry, biology, and engineering. A detailed understanding of the physicochemical processes involved in the flow, structural transitions, and freezing or melting behavior of fluids confined within nanometer-sized pores of solid materials is thus of enormous importance for both basic research and technological applications.This Account provides a perspective on new insights into the thermodynamic and kinetic transitions of nanoconfined fluids in their stable and metastable forms. After briefly introducing the unique properties of mesoporous silicas from the SBA, MCM, and FDU families that serve as the confinement matrices, combining highly ordered single and bimodal mesopore architectures with tunable pore sizes in the ∼2-15 nm range and narrow size distributions, recent studies on melting/freezing behavior of water confined in these host matrices are reviewed. While differential scanning calorimetry (DSC) reveals a linear relationship between melting point depression and pore size (independent of the pore shape), as predicted by the Gibbs-Thomson relation, variable temperature 2H wide-line nuclear magnetic resonance (NMR) spectroscopy studies confirm the core-shell model of water and give evidence for a layer-by-layer freezing mechanism, which gives rise to an apparent fragile-to-strong transition in the solidification dynamics.In contrast to the freezing/melting behavior of water, the effect of nanoconfinement on the glass transition of supercooled liquids is nonuniversal and the glass transition temperature Tg can either increase or decrease with the dimensionality and extent of confinement. This nonuniversal behavior is exemplified by the two glass-forming molecular liquids, glycerol and ortho-terphenyl (OTP). While glycerol shows an increase in Tg and a pronounced slowdown of the rotational dynamics of the constituent molecules due to a change in the molecular packing between the bulk and the confined liquid, OTP displays a linear and confining-media-dependent depression of Tg with increased confinement that is strongly influenced by the pore-liquid interface characteristics.This Account concludes with a focus on recent experimental evidence of extreme spatial and dynamical heterogeneity in both freezing and glass transition processes. This discovery was enabled by the unique mesoporous structures of SBA-16 and FDU-5, possessing bimodal architectures with two interconnected pore types of different size and shape (spherical and cylindrical). For the very first time, two melting points for water and two glass transitions for supercooled OTP, corresponding to a specific pore type, were observed. Collectively, these observations strongly suggest a close mechanistic connection between the local fluctuations in the structure and dynamics of nanoconfined liquids. While the findings reviewed in this Account provide new insights into thermodynamic and kinetic transitions of fluids, there remain many unanswered questions regarding the effects of nanoconfinement on the fundamental properties of fluids, which offer exciting future opportunities in chemical research.

9.
Biochem J ; 477(19): 3803-3818, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-32926159

RESUMO

hTERT, the catalytic component of the human telomerase enzyme, is regulated by post-translational modifications, like phosphorylation and ubiquitination by multiple proteins which remarkably affects the overall activity of the enzyme. Here we report that hTERT gets SUMOylated by SUMO1 and polycomb protein CBX4 acts as the SUMO E3 ligase of hTERT. hTERT SUMOylation positively regulates its telomerase activity which can be inhibited by SENP3-mediated deSUMOylation. Interestingly, we have established a new role of hTERT SUMOylation in the repression of E-cadherin gene expression and consequent triggering on the epithelial-mesenchymal-transition (EMT) program in breast cancer cells. We also observed that catalytically active CBX4, leads to retention of hTERT/ZEB1 complex onto E-cadherin promoter leading to its repression through hTERT-SUMOylation. Further through wound healing and invasion assays in breast cancer cells, we showed the tumor promoting ability of hTERT was significantly compromised upon overexpression of SUMO-defective mutant of hTERT. Thus our findings establish a new post-translational modification of hTERT which on one hand is involved in telomerase activity maintenance and on the other hand plays a crucial role in the regulation of gene expression thereby promoting migration and invasion of breast cancer cells.


Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Movimento Celular , Ligases/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Telomerase/metabolismo , Transcrição Genética , Antígenos CD/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Feminino , Células HeLa , Humanos , Ligases/genética , Células MCF-7 , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas do Grupo Polycomb/genética , Telomerase/genética
10.
Cardiovasc Diabetol ; 19(1): 72, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493344

RESUMO

BACKGROUND: Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population. METHODS: 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30-70 years old), HbA1c of 6.5-10%, CKD Stage 1-3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value < 0.05 considered significant. RESULTS: A double positive CD34/CD184 cell count had a statistically significant increase (p < 0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34- cell mRNA analysis showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p < 0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p < 0.04). Urinary exosome protein examining podocyte health (podocalyxin, Wilms tumor and nephrin) showed reduction or improvement. CONCLUSIONS: In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34 + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks. Trial Registration Number NCT02467478 Date of Registration: 06/08/2015.


Assuntos
Antígenos CD34/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Células Progenitoras Endoteliais/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Linagliptina/uso terapêutico , Metformina/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Biomarcadores/sangue , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/diagnóstico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , District of Columbia , Método Duplo-Cego , Quimioterapia Combinada , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Linagliptina/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Projetos Piloto , Receptores CXCR4/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Fatores de Tempo , Resultado do Tratamento
11.
Stem Cell Res Ther ; 11(1): 250, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32586409

RESUMO

Consumption of non-nutritive sweeteners (NNS) has been consistently associated with obesity and cardiometabolic disease in epidemiologic studies. Herein, we investigated effects of sucralose, a widely used NNS, at a cellular level. We wanted to investigate effect of sucralose on reactive oxygen species accumulation and adipogenesis in a human adipocyte tissue-derived mesenchymal stromal cells (MSCs) in a controlled fashion. METHODS: In vitro experiments were conducted on commercially available MSCs obtained from human adipose tissue. hMSCs were exposed with sucralose at 0.2 mM (a concentration which could plausibly be observed in the circulatory system of high NNS consumers) up to 1.0 mM (supra-physiologic concentration) in the presence of both normal and high glucose media to detect a dose response based on the outcome measures. Reactive oxygen species (ROS) were detected using Mitosox Red staining and further analyzed by ImageJ and gene expression analysis. Effect of sucralose on adipogenic differentiation was observed in different concentrations of sucralose followed by gene expression analysis and Oil Red O staining. RESULTS: Increased ROS accumulation was observed within 72 h of exposure. Increased adipogenesis was also noted when exposed to higher dose of sucralose. CONCLUSION: Sucralose promotes ROS accumulation and adipogenesis in human adipose tissue derived mesenchymal stromal cells.


Assuntos
Adipogenia , Células-Tronco Mesenquimais , Adipócitos , Diferenciação Celular , Células Cultivadas , Humanos , Espécies Reativas de Oxigênio , Sacarose/análogos & derivados
12.
J Am Heart Assoc ; 9(13): e016425, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32564652

RESUMO

Background To identify reasons for increased atherosclerotic risk among women living with HIV (WLWH), we evaluated the associations between psychosocial risk factors (depressive symptoms, perceived stress, and posttraumatic stress disorder symptoms) and subclinical atherosclerosis among WLWH and HIV-negative women. Methods and Results Carotid artery focal plaque (localized intima-media thickness >1.5 mm) was measured using B-mode ultrasound imaging in 2004-2005 and 2010-2012 in the Women's Interagency HIV Study. We created psychosocial risk groups using latent class analysis and defined prevalent plaque at the final measurement. We also examined repeated semiannual depression measures with respect to focal plaque formation throughout follow-up. The associations between latent class and prevalent plaque, and between depressive symptom persistence and plaque formation, were assessed separately by HIV status using multivariable logistic regression. Among 700 women (median age 47 years), 2 latent classes were identified: high (n=163) and low (n=537) psychosocial risk, with corresponding prevalence of depression (65%/13%), high stress (96%/12%), and probable posttraumatic stress disorder (46%/2%). Among WLWH, plaque prevalence was 23% and 11% in high versus low psychosocial risk classes (adjusted odds ratio [aOR], 2.12; 95% CI, 1.11-4.05) compared with 9% and 9% among HIV-negative women (aOR, 1.07; 95% CI, 0.24-4.84), respectively. New plaque formation occurred among 17% and 9% of WLWH who reported high depressive symptoms at ≥45% versus <45% of visits (aOR, 1.96; 95% CI, 1.06-3.64), compared with 9% and 7% among HIV-negative women (aOR, 0.82; 95% CI, 0.16-4.16), respectively. Conclusions Psychosocial factors were independent atherosclerotic risk factors among WLWH. Research is needed to determine whether interventions for depression and psychosocial stress can mitigate the increased risk of atherosclerosis for WLWH.


Assuntos
Doenças das Artérias Carótidas/epidemiologia , Depressão/epidemiologia , Infecções por HIV/epidemiologia , Sobreviventes de Longo Prazo ao HIV/psicologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Estresse Psicológico/epidemiologia , Adulto , Doenças Assintomáticas , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Estudos Transversais , Depressão/diagnóstico , Depressão/psicologia , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/psicologia , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologia , Fatores de Tempo , Estados Unidos/epidemiologia
13.
Sci Rep ; 10(1): 5881, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32246019

RESUMO

Direct quantitative measurements of nanoscale dynamical processes associated with structural relaxation and crystallization near the glass transition are a major experimental challenge. These type of processes have been primarily treated as macroscopic phenomena within the framework of phenomenological models and bulk experiments. Here, we report x-ray photon correlation spectroscopy measurements of dynamics at the crystal-melt interface during the radiation induced formation of Se nano-crystallites in pure Se and in binary AsSe4 glass-forming liquids near their glass transition temperature. We observe a heterogeneous dynamical behaviour where the intensity correlation functions g2(q, t) exhibits either a compressed or a stretched exponential decay, depending on the size of the Se nano-crystallites. The corresponding relaxation timescale for the AsSe4 liquid increases as the temperature is raised, which can be attributed to changes in the chemical composition of the melt at the crystal-melt interface with the growth of the Se nano-crystallites.

14.
Sci Rep ; 10(1): 5208, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251311

RESUMO

The atomic structure of a germanium doped phosphorous selenide glass of composition Ge2.8P57.7Se39.5 is determined as a function of pressure from ambient to 24 GPa using Monte-Carlo simulations constrained by high energy x-ray scattering data. The ambient pressure structure consists primarily of P4Se3 molecules and planar edge shared phosphorus rings, reminiscent of those found in red phosphorous as well as a small fraction of locally clustered corner-sharing GeSe4 tetrahedra. This low-density amorphous phase transforms into a high-density amorphous phase at ~6.3 GPa. The high-pressure phase is characterized by an extended network structure. The polyamorphic transformation between these two phases involves opening of the P3 ring at the base of the P4Se3 molecules and subsequent reaction with red phosphorus type moieties to produce a cross linked structure. The compression mechanism of the low-density phase involves increased molecular packing, whereas that of the high pressure phase involves an increase in the nearest-neighbor coordination number while the bond angle distributions broaden and shift to smaller angles. The entropy and volume changes associated with this polyamorphic transformation are positive and negative, respectively, and consequently the corresponding Clapeyron slope for this transition would be negative. This result has far reaching implications in our current understanding of the thermodynamics of polyamorphic transitions in glasses and glass-forming liquids.

15.
Mol Nutr Food Res ; 64(11): e1901166, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32281732

RESUMO

SCOPE: Low-calorie sweetener (LCS) consumption is associated with metabolic disease in observational studies. However, physiologic mechanisms underlying LCS-induced metabolic impairments in humans are unclear. This study is aimed at identifying molecular pathways in adipose impacted by LCSs. METHODS AND RESULTS: Seven females with overweight or obesity, who did not report LCS use, consumed 12 ounces of diet soda containing sucralose and acesulfame-potassium (Ace-K) three times daily for 8 weeks. A subcutaneous adipose biopsy from the left abdomen and a fasting blood sample were collected at baseline and post-intervention. Global gene expression were assessed using RNA-sequencing followed by functional pathway analysis. No differences in circulating metabolic or inflammatory biomarkers were observed. However, ANOVA detected 828 differentially expressed annotated genes after diet soda consumption (p < 0.05), including transcripts for inflammatory cytokines. Fifty-eight of 140 canonical pathways represented in pathway analyses regulated inflammation, and several key upstream regulators of inflammation (e.g., TNF-alpha) were also represented. CONCLUSION: Consumption of diet soda with sucralose and Ace-K alters inflammatory transcriptomic pathways (e.g., NF-κB signaling) in subcutaneous adipose tissue but does not significantly alter circulating biomarkers. Findings highlight the need to examine molecular and metabolic effects of LCS exposure in a larger randomized control trial for a longer duration.

16.
J Diabetes Complications ; 34(7): 107588, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32345465

RESUMO

Diabetes affects approximately 10.5% of adults in the United States and this is projected to nearly double by 2025. Both type 2 diabetes (T2DM) and obesity are associated with endothelial dysfunction, oxidative stress, endothelial cell inflammation, cardiovascular pro-thrombotic states and are the most common causes of endothelial dysfunction, chronic kidney disease (CKD) and cardiovascular disease (CVD). Lately several new diabetes medications have come to clinical use that claim CVD risk improvement, however modalities used to test and monitor CVD risk are not cell based, which bring into question the reproducibility of these studies. Our review is designed to highlight cardiovascular risk reduction with novel diabetes medications while emphasizing cellular outcomes as a biomarker of cardiovascular risk. We are going to highlight studies that comment on peripheral blood derived CD34+ hematopoietic progenitor cells, as biomarkers of endothelial function. CD34+ cells have been extensively investigated by us and several other laboratories for the last two decades, as a viable cardiovascular function biomarker. In this context we will also discuss relevant CVD risk reduction trials that used novel diabetes medications.

17.
Prog Nucl Magn Reson Spectrosc ; 116: 155-176, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32130956

RESUMO

Dynamical NMR spectroscopy provides unique mechanistic understanding of the transport and relaxation processes in glass-forming liquids over timescales typically ranging from ~10-9 s to ~102 s, and thus has been used extensively in the past to study the dynamical behavior of polymeric and organic glass-forming liquids. However, reports in the literature of similar studies on inorganic glass-forming liquids have remained somewhat limited due to the experimental challenges. In this contribution we present a review of the high-temperature NMR spectroscopic studies of atomic and molecular dynamics in a wide variety of inorganic glass-forming liquids including oxides, halides and chalcogenides as well as select ionic liquids and molten salts. The significance of these dynamical processes in understanding the nature of the liquid-to-glass transition and their connection with the macroscopic transport properties of these liquids are discussed.

18.
Sci Rep ; 10(1): 5327, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210285

RESUMO

Nanoconfined water plays a pivotal role in a vast number of fields ranging from biological and materials sciences to catalysis, nanofluidics and geochemistry. Here, we report the freezing and melting behavior of water (D2O) nanoconfined in architected silica-based matrices including Vycor glass and mesoporous silica SBA-15 and SBA-16 with pore diameters ranging between 4-15 nm, which are investigated using differential scanning calorimetry and 2H nuclear magnetic resonance spectroscopy. The results provide compelling evidence that the extreme dynamical heterogeneity of water molecules is preserved over distances as small as a few angstroms. Solidification progresses in a layer-by-layer fashion with a coexistence of liquid-like and solid-like dynamical fraction at all temperatures during the transition process. The previously reported fragile-to-strong dynamic transition in nanoconfined water is argued to be a direct consequence of the layer-by-layer solidification.

19.
Science ; 367(6485): 1473-1476, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32217725

RESUMO

The structure of melt-quenched zeolitic imidazole framework (ZIF) glasses can provide insights into their glass-formation mechanism. We directly detected short-range disorder in ZIF glasses using ultrahigh-field zinc-67 solid-state nuclear magnetic resonance spectroscopy. Two distinct Zn sites characteristic of the parent crystals transformed upon melting into a single tetrahedral site with a broad distribution of structural parameters. Moreover, the ligand chemistry in ZIFs appeared to have no controlling effect on the short-range disorder, although the former affected their phase-transition behavior. These findings reveal structure-property relations and could help design metal-organic framework glasses.

20.
J Chem Phys ; 152(4): 044502, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32007069

RESUMO

The dynamics of the phosphate chains and the attendant shear relaxation in a short-chain silver phosphate glass-forming liquid with the composition 51.5%Ag2O-48.5% P2O5 are studied using a combination of high-temperature 31P NMR spectroscopy and parallel plate rheometry. The temperature-dependent evolution of the 31P NMR spectral line shapes indicates that the constituent PO4 tetrahedral chains in this liquid undergo rapid rotational reorientation. The time scale of this dynamics is in complete agreement with that of shear relaxation and, thus, must be responsible for the viscous flow of this liquid. These results demonstrate for the first time that, although the shear relaxation of the network oxide glass-forming liquids is typically controlled by the scission and renewal of bonds between the network-forming cations and oxygen atoms, such a scenario may not always be tenable for liquids with low-dimensional structures consisting of chains.

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