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1.
Int J Mol Sci ; 21(7)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244266

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPARα transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of triglycerides within the hepatocytes. Interestingly, a reciprocal regulation of PPARα nuclear action by autophagy-lysosomal activity also exists with implications in lipid metabolism. This review succinctly discusses the unique relationship between PPARα nuclear action and lysosomal activity and explores its impact on hepatic lipid homeostasis under pathological conditions such as non-alcoholic fatty liver disease (NAFLD).

2.
Virus Res ; 282: 197936, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234325

RESUMO

Vitamin D3/Calcitriol supplementation in humans is associated with reduced incidence and severity during influenza A virus (IAV) infection. Apoptosis in response to IAV infection is a major contributor to host cell death and tissue damage; however, its modulation by Vitamin D3 remains unclear. In this study, we demonstrate the efficacy of Vitamin D3 in preventing apoptosis induction by pandemic influenza A (H1N1)pdm09 virus in human alveolar cells (A549). Human alveolar epithelial cell line A549 was used to assess the cytotoxic effects of IAV infection. Immunoblotting and fluorescence microscopy were used to study apoptosis and autophagy. The results of the present study demonstrate that IAV induces apoptosis by subversion of host autophagy via down-regulating components of autophagic machinery involved in autophagosome-lysosome fusion and lysosomal activity. Vitamin D3 restores the autophagic flux inhibited by IAV by upregulating the expression of Syntaxin-17 (STX17) and V-type proton ATPase subunit (ATP6V0A2) thereby causing a concomitant decrease in cellular apoptosis via a Vitamin D3 receptor (VDR) dependent mechanism. The present study suggests that Vitamin D3 is a potentially useful agent for limiting IAV-induced cellular injury via its pro-autophagic action.

3.
Exp Mol Pathol ; 114: 104413, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32151561

RESUMO

Maternal inflammation ensuing from high-fat diet (HFD) intake during pregnancy is related to spontaneous preterm birth and respiratory impairment among premature infants. Recently, a circadian aligned dietary intervention referred to as Time-restricted feeding (TRF) has been reported to have beneficial metabolic effects. This study aimed to assess the effects of maternal TRF on fetal lung injury caused by maternal HFD intake. Female Wistar rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months before mating and continued through pregnancy. Fetal lung samples were collected on the embryonic day 18.5, and apoptotic and inflammatory markers were assessed using TUNEL assay, western blotting, and qRT-PCR. Our results showed that TRF considerably prevented maternal HFD-induced apoptosis in fetal lung tissue that corroborated with a reduction in caspase activation and increased levels of anti-apoptotic BCL2 family proteins together with a lower level of ER-stress and autophagy markers including ATF6, CHOP and LC3-II. Besides, fetal lungs from HFD-TRF dams exhibited reduced expression of inflammatory genes that correlated with reduction and apoptotic injury throughout fetal development. Our results thus put forth TRF as a unique non-pharmacological approach to boost perinatal health beneath metabolic stress.

4.
J Endocrinol ; 244(1): 53-70, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648182

RESUMO

Estrogen deficiency reduces estrogen receptor-alpha (ERα) and promotes apoptosis in the hippocampus, inducing learning-memory deficits; however, underlying mechanisms remain less understood. Here, we explored the molecular mechanism in an ovariectomized (OVX) rat model, hypothesizing participation of autophagy and growth factor signaling that relate with apoptosis. We observed enhanced hippocampal autophagy in OVX rats, characterized by increased levels of autophagy proteins, presence of autophagosomes and inhibition of AKT-mTOR signaling. Investigating upstream effectors of reduced AKT-mTOR signaling revealed a decrease in hippocampal heparin-binding epidermal growth factor (HB-EGF) and p-EGFR. Moreover, 17ß-estradiol and HB-EGF treatments restored hippocampal EGFR activation and alleviated downstream autophagy process and neuronal loss in OVX rats. In vitro studies using estrogen receptor (ERα)-silenced primary hippocampal neurons further corroborated the in vivo observations. Additionally, in vivo and in vitro studies suggested the participation of an attenuated hippocampal neuronal HB-EGF and enhanced autophagy in apoptosis of hippocampal neurons in estrogen- and ERα-deficient conditions. Subsequently, we found evidence of mitochondrial loss and mitophagy in hippocampal neurons of OVX rats and ERα-silenced cells. The ERα-silenced cells also showed a reduction in ATP production and an HB-EGF-mediated restoration. Finally in concordance with molecular studies, inhibition of autophagy and treatment with HB-EGF in OVX rats restored cognitive performances, assessed through Y-Maze and passive avoidance tasks. Overall, our study, for the first time, links neuronal HB-EGF/EGFR signaling and autophagy with ERα and memory performance, disrupted in estrogen-deficient condition.

5.
Thyroid ; 29(9): 1173-1191, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31389309

RESUMO

Background: Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary: THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor ß analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-l-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions: TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.

6.
J Hosp Infect ; 103(3): 280-283, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31170422

RESUMO

The aim of the study was to assess antimicrobial prescribing patterns, and variation in practice, in India. A point prevalence survey (PPS) was conducted in October to December 2017 in 16 tertiary care hospitals across India. The survey included all inpatients receiving an antimicrobial on the day of PPS and collected data were analysed using a web-based application of the University of Antwerp. In all, 1750 patients were surveyed, of whom 1005 were receiving a total of 1578 antimicrobials. Among the antimicrobials prescribed, 26.87% were for community-acquired infections; 19.20% for hospital-acquired infections; 17.24% for medical prophylaxis; 28.70% for surgical prophylaxis; and 7.99% for other or undetermined reasons. Antibiotic prescribing quality indicators, such as reason in notes and post-prescription review score, were low. This PPS showed widespread antibiotic usage, underlining the need for antibiotic stewardship to promote evidence-based practice.


Assuntos
Antibacterianos/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Humanos , Índia , Inquéritos e Questionários , Centros de Atenção Terciária
7.
Biochem Biophys Res Commun ; 514(2): 415-421, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31053302

RESUMO

Maternal nutrition has become a major public health concern over recent years and is a known predictor of adverse long-term metabolic derangement in offspring. Time-restricted feeding (TRF), wherein food consumption is restricted to the metabolically active phase of the day, is a dietary approach that improves metabolic parameters when consuming a high-fat diet (HFD). Here, we tested whether TRF could reduce maternal HFD associated inflammation and thereby mitigate defects in fetal organ developmental. Female rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months prior to mating and continued throughout pregnancy. Rat dams were sacrificed at embryonic day 18.5 (ED18.5) and placental tissues from these rats were processed for the analysis of cellular apoptosis, inflammatory cytokines (TNFα and IL-6), oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Furthermore, fetal hepatic triglyceride (TG) content and fetal lung maturation were assessed at ED18.5. Biochemical analysis revealed that HFD-TRF rat had significantly lower serum TG levels and body weight compared to HFD-AL rats. Additionally, TRF significantly blocked HFD-induced placental apoptosis and inflammation via minimizing cellular stress, and restoring autophagic flux. In addition, fetal hepatosteatosis and delayed fetal lung maturation induced by HFD was significantly ameliorated in HFD-TRF compared to HFD-AL. Collectively, our results suggest that reducing placental inflammation via TRF could prevent adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.

8.
Gastroenterology ; 157(3): 777-792.e14, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078624

RESUMO

BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.


Assuntos
Anticorpos Neutralizantes/farmacologia , Hepatite/prevenção & controle , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1
9.
Open Access Maced J Med Sci ; 7(6): 1042-1046, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30976358

RESUMO

BACKGROUND: The molar incisor hypomineralization (MIH) is defined as a qualitative defect of the enamel characterised by the progressive and simultaneous hypomineralization of the enamel structure of the first permanent molars which is of systemic origin, which may be associated frequently with incisors. Although the reported prevalence of MIH ranges from 2.4% to 40.2% worldwide, very little data is available from India. AIM: To determine the prevalence of molar incisor hypomineralization among school children aged 9 to 12 years in virajpet, Karnataka. METHODS: This cross-sectional descriptive study consisted of 1600 school children aged 9-12 years selected by stratified cluster sampling procedure. The European Academy of Pediatric Dentistry criteria were followed for MIH diagnosis. Chi-square test was used to analyse the categorical data. P ≤ 0.05 was considered for statistical significance. RESULTS: The prevalence of MIH is 13.12% with no gender predilection. Ten-year-old children showed the highest prevalence (15%) among all the age group. Majority of children with MIH (70.2%) have lesions in both molars and incisors with demarcated opacities and atypical restorations being the most frequent defect type. CONCLUSION: Prevalence of MIH was 13.12% in the 9-12-year child population in Virajpet. There is a need for a proper planned preventive and restorative program about the increasing prevalence of MIH.

10.
Autophagy ; 15(8): 1455-1459, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31032705

RESUMO

Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cell line, AML12, treated with bafilomycin A1 (lysosomal v-type H+-translocating ATPase inhibitor). Pathway enrichment analysis revealed significant downregulation of gene sets related to peroxisomal biogenesis and peroxisomal lipid oxidation upon lysosomal inhibition. Mechanistically, pharmacological inhibition of lysosomes as well as genetic knockdown of Tfeb led to downregulation of the peroxisomal master regulator PPARA and its coactivator PPARGC1A/PGC1α. Consistently, ectopic induction of PPARA transcriptional activity rescues the effects of lysosomal inhibition on peroxisomal gene expression. Collectively, our results uncover a novel metabolic regulation of peroxisomes by lysosomes via PPARA-PPARGC1A transcriptional signalling. Abbreviations: Acox1: acyl-Coenzyme A oxidase 1, palmitoyl; Acot: acyl-CoA thioesterase; ACAA: acetyl-Coenzyme A acyltransferase; ABCD3/PMP70: ATP-binding cassette, sub-family D (ALD), member 3; BafA1: bafilomycin A1; Crot: carnitine O-octanoyltransferase; CTSB: cathepsin B; Decr2: 2-4-dienoyl-Coenzyme A reductase 2, peroxisomal; Ech1: enoyl coenzyme A hydratase 1, peroxisomal; Ehhadh: enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase; FDR: false discovery rate; Hsd17b4: hydroxysteroid (17-beta) dehydrogenase 4; NES: normalized enrichment score; NOM: nominal; Pex: peroxin; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; TFEB: transcription factor EB.

11.
NPJ Genom Med ; 4: 7, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962949

RESUMO

The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.

12.
Prog Orthod ; 20(1): 14, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30957212

RESUMO

BACKGROUND: The use of face mask for early treatment of class III malocclusion has proven to be successful, but its compliance and related dental side effects have always been a problem. To overcome this, a new approach has been suggested. The purpose of the present study was to compare the effectiveness of reverse twin block with lip pads and fixed rapid maxillary expansion (RTBLP-RME) appliance and face mask with RME (FM-RME) appliance for early treatment of class III malocclusion. METHODS: The sample consisted of 39 patients with class III malocclusion in the age group of 6-12 years (mean 10.17). They were divided into 3 groups of 13 each: reverse twin block with lip pads-RME (RTBLP-RME), face mask with RME (FM-RME), and control group. Treatment time was 9 months. Lateral cephalograms were taken at the start of treatment (T1) and after 9 months (T2) (both groups). RESULTS: Both appliances were effective in correction of class III malocclusion with significant (p < 0.01) changes in all the cephalometric variables except cranial base angulations as compared to the control group. Intergroup comparison showed nonsignificant but greater sagittal changes with RTBLP-RME as compared to the FM-RME group. For all vertical measurements, the RTBLP-RME group showed nonsignificant increase compared to the FM-RME group. Maxillary incisor proclination was less in the RTBLP-RME group than in the FM-RME group, while mandibular incisor proclination was more in the RTBLP-RME group. Condylar inclination was significantly (p < 0.01) different for both treatment groups. With the RTBLP-RME group, posterior inclination of the condyle was seen while the FM-RME group showed more forward positioning as compared to the control group. CONCLUSION: Both groups were effective in correcting the malocclusion, but RTBLP-RME appliance had nonsignificant but greater impact on maxillary advancement and more hold on the posterior positioning of the mandible with minimal dental compensation as compared to FM-RME appliance.


Assuntos
Lábio , Má Oclusão de Angle Classe III , Cefalometria , Criança , Aparelhos de Tração Extrabucal , Humanos , Mandíbula , Maxila , Técnica de Expansão Palatina , Resultado do Tratamento
13.
Biochem Pharmacol ; 164: 34-44, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30885766

RESUMO

Liraglutide (Lira), a long-acting glucagon-like peptide 1 receptor (GLP1R) agonist reduces glycosylated hemoglobin in type 2 diabetes mellitus patients. Lira is reported to have bone conserving effect in ovariectomized (OVX) rats. Here, we investigated the osteoanabolic effect of Lira and studied the underlying mechanism. In established osteopenic OVX rats, Lira completely restored bone mass and strength comparable to parathyroid hormone (PTH 1-34). Body mass index normalized bone mineral density of Lira was higher than PTH. The serum levels of osteogenic surrogate pro-collagen type 1 N-terminal pro-peptide (P1NP) and surface referent bone formation parameters were comparable between Lira and PTH. GLP1R, adiponectin receptor 1 (AdipoR1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) levels in bones were downregulated in the OVX group but restored in the Lira group whereas PTH had no effect. In cultured osteoblasts, Lira time-dependently increased GLP1R, AdipoR1 and PGC1α expression. In osteoblasts, Lira rapidly phosphorylated AMP-dependent protein kinase (AMPK), the cellular energy sensor. Exendin 3, a selective GLP1R antagonist and PKA inhibitor H89 blocked Lira-induced increases in osteoblast differentiation, and expression levels of AdipoR1 and PGC1α. Furthermore, H89 inhibited Lira-induced phosphorylation of AMPK and dorsomorphin, an AMPK inhibitor blocked the Lira-induced increases in osteoblast differentiation and AdipoR1 and PGC1α levels. Lira increased mitochondrial number, respiratory proteins and respiration in osteoblasts in vitro and in vivo, and blocking mitochondrial respiration mitigated Lira-induced osteoblast differentiation. Taken together, our data show that Lira has a strong osteoanabolic effect which involves upregulation of mitochondrial function.


Assuntos
Densidade Óssea/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Mitocôndrias/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Densidade Óssea/fisiologia , Células Cultivadas , Feminino , Mitocôndrias/metabolismo , Osteoblastos/metabolismo , Osteogênese/fisiologia , Ovariectomia/efeitos adversos , Ratos , Ratos Sprague-Dawley
14.
Hum Mol Genet ; 28(12): 1971-1981, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30715350

RESUMO

Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy. TTNtv occur in ~1% of the general population and causes subclinical cardiac remodeling in asymptomatic carriers. In rat models with either proximal or distal TTNtv, we previously showed altered cardiac metabolism at baseline and impaired cardiac function in response to stress. However, the molecular mechanism(s) underlying these effects remains unknown. In the current study, we used rat models of TTNtv to investigate the effect of TTNtv on autophagy and mitochondrial function, which are essential for maintaining cellular metabolic homeostasis and cardiac function. In both the proximal and distal TTNtv rat models, we found increased levels of LC3B-II and p62 proteins, indicative of diminished autophagic degradation. The accumulation of autophagosomes and p62 protein in cardiomyocytes was also demonstrated by electron microscopy and immunochemistry, respectively. Impaired autophagy in the TTNtv heart was associated with increased phosphorylation of mTOR and decreased protein levels of the lysosomal protease, cathepsin B. In addition, TTNtv hearts showed mitochondrial dysfunction, as evidenced by decreased oxygen consumption rate in cardiomyocytes, increased levels of reactive oxygen species and mitochondrial protein ubiquitination. We also observed increased acetylation of mitochondrial proteins associated with decreased NAD+/NADH ratio in the TTNtv hearts. mTORC1 inhibitor, rapamycin, was able to rescue the impaired autophagy in TTNtv hearts. In summary, TTNtv leads to impaired autophagy and mitochondrial function in the heart. These changes not only provide molecular mechanisms that underlie TTNtv-associated ventricular remodeling but also offer potential targets for its intervention.


Assuntos
Autofagia/genética , Cardiomiopatia Dilatada/genética , Conectina/genética , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Acetilação , Animais , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Cardiomiopatia Dilatada/metabolismo , Catepsina B/metabolismo , Células Cultivadas , Conectina/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias Cardíacas/patologia , Proteínas Mitocondriais/metabolismo , NAD/análogos & derivados , NAD/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Deleção de Sequência , Proteína Sequestossoma-1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ubiquitinação
15.
J Med Econ ; 22(5): 471-477, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30744455

RESUMO

OBJECTIVES: To determine how overall cost of anticoagulation therapy for warfarin compares with that of Novel Oral Anticoagulants (NOACs). Also, to demonstrate a scientific, comprehensive, and an analytical approach to estimate direct costs involved in monitoring and management of anticoagulation therapy for outpatients in an academic primary care clinic setting, post-initiation of therapy. METHODS: A population-based cross-sectional study was conducted in conjunction with observations of patient care processes between August 2014 and January 2015. The study was conducted in an academic primary care outpatient setting at Mayo Clinic's warfarin anticoagulation clinic, Rochester, MN. The anticoagulation clinic serves patients 18 years of age or older in Warfarin therapy management, for any indication, after referral from the patient's primary care provider. The study included anticoagulation clinic enrollment data on a population of 5,526 patients. Time-Driven Activity-Based Costing (TDABC) technique was applied. Detailed process flow maps which showed process steps for all the anticoagulation program components and care continuum phases were created. Staff roles associated with each of the process steps were identified and displayed on the maps. Process times and costs were captured and analyzed. The main outcome was direct cost of monitoring and management of anticoagulation therapy, post-initiation of therapy. RESULTS: The cost of warfarin management for patients who display unstable International Normalized Ratio (INR) is more than three times those who display stable INR over time. (Comparator to distinguish stability: Frequency of point-of-care visits needed by patients.) For complex anticoagulation patients, total cost of medication and monitoring for warfarin anticoagulation therapy is similar to that for NOACs. CONCLUSION: Despite warfarin being significantly less expensive to purchase than NOACs, overall warfarin management incurs higher costs due to laboratory monitoring and provider time than NOACs. NOAC treatment, therefore, may not be more expensive than warfarin therapy management for complex anticoagulation patients.


Assuntos
Anticoagulantes/economia , Fibrilação Atrial/tratamento farmacológico , Monitoramento de Medicamentos/economia , Monitoramento de Medicamentos/estatística & dados numéricos , Centros Médicos Acadêmicos/economia , Centros Médicos Acadêmicos/estatística & dados numéricos , Instituições de Assistência Ambulatorial/economia , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Anticoagulantes/uso terapêutico , Custos e Análise de Custo , Estudos Transversais , Feminino , Pessoal de Saúde/economia , Humanos , Coeficiente Internacional Normatizado/economia , Coeficiente Internacional Normatizado/estatística & dados numéricos , Masculino , Varfarina/economia , Varfarina/uso terapêutico
16.
Autophagy ; 15(1): 131-150, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30209975

RESUMO

The thyroid hormone triiodothyronine (T3) activates thermogenesis by uncoupling electron transport from ATP synthesis in brown adipose tissue (BAT) mitochondria. Although T3 can induce thermogenesis by sympathetic innervation, little is known about its cell autonomous effects on BAT mitochondria. We thus examined effects of T3 on mitochondrial activity, autophagy, and metabolism in primary brown adipocytes and BAT and found that T3 increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis. Interestingly, there was no significant induction of intracellular reactive oxygen species (ROS) despite high mitochondrial respiration and UCP1 induction by T3. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T3 decreased, and was accompanied by ROS accumulation, demonstrating a critical role for autophagic mitochondrial turnover. We next generated an Atg5 conditional knockout mouse model (Atg5 cKO) by injecting Ucp1 promoter-driven Cre-expressing adenovirus into Atg5Flox/Flox mice to examine effects of BAT-specific autophagy on thermogenesis in vivo. Hyperthyroid Atg5 cKO mice exhibited lower body temperature than hyperthyroid or euthyroid control mice. Metabolomic analysis showed that T3 increased short and long chain acylcarnitines in BAT, consistent with increased ß-oxidation. T3 also decreased amino acid levels, and in conjunction with SIRT1 activation, decreased MTOR activity to stimulate autophagy. In summary, T3 has direct effects on mitochondrial autophagy, activity, and turnover in BAT that are essential for thermogenesis. Stimulation of BAT activity by thyroid hormone or its analogs may represent a potential therapeutic strategy for obesity and metabolic diseases. Abbreviations: ACACA: acetyl-Coenzyme A carboxylase alpha; AMPK: AMP-activated protein kinase; Acsl1: acyl-CoA synthetase long-chain family member 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; BAT: brown adipose tissue; cKO: conditional knockout; COX4I1: cytochrome c oxidase subunit 4I1; Cpt1b: carnitine palmitoyltransferase 1b, muscle; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DIO2: deiodinase, iodothyronine, type 2; DMEM: Dulbecco's modified Eagle's medium; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; Fabp4: fatty acid binding protein 4, adipocyte; FBS: fetal bovine serum; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FGF: fibroblast growth factor; FOXO1: forkhead box O1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Gpx1: glutathione peroxidase 1; Lipe: lipase, hormone sensitive; MAP1LC3B: microtubule-associated protein 1 light chain 3; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; NAD: nicotinamide adenine dinucleotide; Nrf1: nuclear respiratory factor 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; Pnpla2: patatin-like phospholipase domain containing 2; Prdm16: PR domain containing 16; PRKA: protein kinase, AMP-activated; RPS6KB: ribosomal protein S6 kinase; RFP: red fluorescent protein; ROS: reactive oxygen species; SD: standard deviation; SEM: standard error of the mean; siRNA: small interfering RNA; SIRT1: sirtuin 1; Sod1: superoxide dismutase 1, soluble; Sod2: superoxide dismutase 2, mitochondrial; SQSTM1: sequestosome 1; T3: 3,5,3'-triiodothyronine; TFEB: transcription factor EB; TOMM20: translocase of outer mitochondrial membrane 20; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); ULK1: unc-51 like kinase 1; VDAC1: voltage-dependent anion channel 1; WAT: white adipose tissue.

17.
Biochem Biophys Res Commun ; 506(3): 597-603, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30366665

RESUMO

Hypothyroidism has been associated with better recovery from cerebral ischemia-reperfusion (IR) injury in humans. However, any therapeutic advantage of inducing hypothyroidism for mitigating IR injury without invoking the adverse effect of whole body hypothyroidism remains a challenge. We hypothesize that a deiodinase II (D2) inhibitor reverse triiodothyronine (rT3) may render brain specific hypometabolic state to ensue reduced damage during an acute phase of cerebral ischemia without affecting circulating thyroid hormone levels. Preclinical efficacy of rT3 as a neuroprotective agent was determined in rat model of middle cerebral artery occlusion (MCAO) induced cerebral IR and in oxygen glucose deprivation/reoxygenation (OGD/R) model in vitro. rT3 administration in rats significantly reduced neuronal injury markers, infarct size and neurological deficit upon ischemic insult. Similarly, rT3 increased cellular survival in primary cerebral neurons under OGD/R stress. Based on our results from both in vivo as well as in vitro models of ischemia reperfusion injury we propose rT3 as a novel therapeutic agent in reducing neuronal damage and improving stroke outcome.


Assuntos
Traumatismo por Reperfusão/tratamento farmacológico , Tri-Iodotironina Reversa/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Glucose/deficiência , Frequência Cardíaca/efeitos dos fármacos , Iodeto Peroxidase/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/prevenção & controle , Tri-Iodotironina Reversa/farmacologia
18.
Dis Colon Rectum ; 61(10): 1196-1204, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30192328

RESUMO

BACKGROUND: Multimodal pain management is an integral part of enhanced recovery pathways. The most effective pain management strategies have not been determined. OBJECTIVE: The purpose of this study was to compare liposomal bupivacaine transversus abdominis plane block with epidural analgesia in patients undergoing colorectal surgery. DESIGN: This is a single-institution, open-label randomized (1:1) trial. SETTING: This study compared liposomal bupivacaine transversus abdominis plane block with epidural analgesia in patients undergoing elective open and minimally invasive colorectal surgery in an enhanced recovery pathway. PATIENTS: Two hundred were enrolled. Following randomization, allocation, and follow-up, there were 92 patients with transversus abdominis plane block and 87 patients with epidural analgesia available for analysis. INTERVENTIONS: The interventions comprised liposomal bupivacaine transversus abdominis plane block versus epidural analgesia. MAIN OUTCOME MEASURES: The primary outcomes measured were numeric pain scores and the overall benefit of analgesia scores. RESULTS: There were no significant differences in the Numeric Pain Scale and Overall Benefit of Analgesia Score between groups. Time trend analysis revealed that patients with transversus abdominis plane block had higher numeric pain scores on the day of surgery, but that the relationship was reversed later in the postoperative period. Opioid use was significantly less in the transversus abdominis plane block group (206.84 mg vs 98.29 mg, p < 0.001). There were no significant differences in time to GI recovery, hospital length of stay, and postoperative complications. Cost was considerably more for the epidural analgesia group. LIMITATIONS: This study was conducted at a single institution. CONCLUSIONS: This randomized trial shows that perioperative pain management with liposomal bupivacaine transversus abdominis plane block is as effective as epidural analgesia and is associated with less opioid use and less cost. These data and the more favorable risk profile suggest that liposomal bupivacaine transversus abdominis plane block is a viable multimodal perioperative pain management option for this patient population in an established enhanced recovery pathway. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT02591407). See Video Abstract at http://links.lww.com/DCR/A737.


Assuntos
Músculos Abdominais/efeitos dos fármacos , Analgesia Epidural/métodos , Bupivacaína/farmacologia , Colo/cirurgia , Cirurgia Colorretal/normas , Bloqueio Nervoso/métodos , Dor Pós-Operatória/tratamento farmacológico , Músculos Abdominais/inervação , Músculos Abdominais/fisiopatologia , Adulto , Analgesia Epidural/economia , Analgesia Epidural/estatística & dados numéricos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Bupivacaína/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Manejo da Dor/normas , Medição da Dor/métodos , Assistência Perioperatória/normas , Período Pós-Operatório
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