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1.
Artigo em Inglês | MEDLINE | ID: mdl-34619367

RESUMO

Eicosapentaenoic acid (EPA) ethyl esters are of interest given their clinical approval for lowering circulating triglycerides and cardiometabolic disease risk. EPA ethyl esters prevent metabolic complications driven by a high fat diet in male mice; however, their impact on female mice is less studied. Herein, we first investigated how EPA influences the metabolic profile of female C57BL/6J mice consuming a high fat diet. EPA lowered murine fat mass accumulation, potentially through increased biosynthesis of 8-hydroxyeicosapentaenoic acid (HEPE), as revealed by mass spectrometry and cell culture studies. EPA also reversed the effects of a high fat diet on circulating levels of insulin, glucose, and select inflammatory/metabolic markers. Next, we studied if the improved metabolic profile of obese mice consuming EPA was associated with a reduction in the abundance of key gut Gram-negative bacteria that contribute toward impaired glucose metabolism. Using fecal 16S-ribosomal RNA gene sequencing, we found EPA restructured the gut microbiota in a time-dependent manner but did not lower the levels of key Gram-negative bacteria. Interestingly, EPA robustly increased the abundance of the Gram-negative Akkermansia muciniphila, which controls glucose homeostasis. Finally, predictive functional profiling of microbial communities revealed EPA-mediated reversal of high fat diet-associated changes in a wide range of genes related to pathways such as Th-17 cell differentiation and PI3K-Akt signaling. Collectively, these results show that EPA ethyl esters prevent some of the deleterious effects of a high fat diet in female mice, which may be mediated mechanistically through 8-HEPE and the upregulation of intestinal Akkermansia muciniphila.

2.
Mol Nutr Food Res ; : e2100274, 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510720

RESUMO

SCOPE: Obesity prevalence continues to increase and contribute to metabolic diseases, potentially by driving systemic inflammation. Curcumin is an anti-inflammatory spice with claimed health benefits. However, mechanisms by which curcumin may reduce obesity-associated inflammation are poorly understood; thus, it is hypothesized that benefits of curcumin consumption may occur through reduced white adipose tissue (WAT) inflammation and/or beneficial changes in gut bacteria. METHODS AND RESULTS: Male B6 mice are fed high-fat diets (HFD, 45% kcal fat) or HFD supplemented with 0.4% (w/w) curcumin (HFC) for 14 weeks. Curcumin supplementation significantly reduces adiposity and total macrophage infiltration in WAT, compared to HFD group, consistent with reduced mRNA levels of M1 (Cd80, Cd38, Cd11c) and M2 (Arginase-1) macrophage markers. Moreover, curcumin supplementation reduces expression of other key pro-inflammatory genes, such as NF-κB p65 subunit (p65), Stat1, Tlr4, and Il6, in WAT (p < 0.05). Using microbial 16S RNA sequencing, it is demonstrated that the relative abundance of the Lactococcus, Parasutterella, and Turicibacter genera are increased in the HFC group versus HFD. CONCLUSIONS: Curcumin exerts protective metabolic effects in dietary obesity, in part through downregulation of adipose tissue inflammation, which may be mediated by alterations in composition of gut microbiota, and metabolism of curcumin into curcumin-O-glucuronide.

3.
Cells ; 10(8)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34440735

RESUMO

Knowledge regarding complex radiation responses in biological systems can be enhanced using genetically amenable model organisms. In this manuscript, we reviewed the use of the nematode, Caenorhabditis elegans (C. elegans), as a model organism to investigate radiation's biological effects. Diverse types of experiments were conducted on C. elegans, using acute and chronic exposure to different ionizing radiation types, and to assess various biological responses. These responses differed based on the type and dose of radiation and the chemical substances in which the worms were grown or maintained. A few studies compared responses to various radiation types and doses as well as other environmental exposures. Therefore, this paper focused on the effect of irradiation on C. elegans, based on the intensity of the radiation dose and the length of exposure and ways to decrease the effects of ionizing radiation. Moreover, we discussed several studies showing that dietary components such as vitamin A, polyunsaturated fatty acids, and polyphenol-rich food source may promote the resistance of C. elegans to ionizing radiation and increase their life span after irradiation.

4.
J Nutr Biochem ; 98: 108819, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34271101

RESUMO

Brown adipose tissue (BAT) plays a key role in energy expenditure through its thermogenic function, making its activation a popular target to reduce obesity. We recently reported that male mice housed at thermoneutrality with uncoupling protein 1 (UCP1) deficiency had increased weight gain and glucose intolerance, but eicosapentaenoic acid (EPA) ameliorated these effects. Whether female mice respond similarly to lack of UCP1 and to EPA remains unknown. We hypothesize that the effects of EPA on BAT activation are independent of UCP1 expression. We used female wild type (WT) and UCP1 knockout (KO) mice housed at thermoneutrality (30°C) as an obesogenic environment and fed them high fat (HF) diets with or without EPA for up to 14 weeks. Body weight (BW), body composition, and insulin and glucose tolerance tests were performed during the feeding trial. At termination, serum and BAT were harvested for further analyses. Mice in the KO-EPA group had significantly lower BW than KO-HF mice. In addition, KO-HF mice displayed significantly impaired glucose tolerance compared to their WT-HF littermates. However, EPA significantly enhanced glucose clearance in the KO mice compared to KO-HF mice. Protein levels of the mitochondrial cytochrome C oxidase subunits I, II, and IV were significantly lower in KO mice compared to WT. Our findings support that ablation of UCP1 is detrimental to energy metabolism of female mice in thermoneutral conditions. However, unexpectedly, EPA's protective effects against diet-induced obesity and glucose intolerance in these mice were independent of UCP1.

5.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207035

RESUMO

Breast cancer is the most commonly occurring cancer in women of Western countries and is the leading cause of cancer-related mortality. The breast tumor microenvironment contains immune cells, fibroblasts, adipocytes, mesenchymal stem cells, and extracellular matrix. Among these cells, macrophages or tumor-associated macrophages (TAMs) are the major components of the breast cancer microenvironment. TAMs facilitate metastasis of the breast tumor and are responsible for poor clinical outcomes. High TAM density was also found liable for the poor prognosis of breast cancer. These observations make altering TAM function a potential therapeutic target to treat breast cancer. The present review summarizes the origin of TAMs, mechanisms of macrophage recruitment and polarization in the tumor, and the contributions of TAMs in tumor progression. We have also discussed our current knowledge about TAM-targeted therapies and the roles of miRNAs and exosomes in re-educating TAM function.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Comunicação Celular , Progressão da Doença , Suscetibilidade a Doenças , Exossomos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Imunomodulação , Ativação de Macrófagos/imunologia , MicroRNAs/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Carga Tumoral , Macrófagos Associados a Tumor/patologia
6.
Crit Rev Biochem Mol Biol ; 56(5): 455-481, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34182855

RESUMO

Over accumulation of lipids in adipose tissue disrupts metabolic homeostasis by affecting cellular processes. Endoplasmic reticulum (ER) stress is one such process affected by obesity. Biochemical and physiological alterations in adipose tissue due to obesity interfere with adipose ER functions causing ER stress. This is in line with increased irregularities in other cellular processes such as inflammation and autophagy, affecting overall metabolic integrity within adipocytes. Additionally, microRNAs (miRNAs), which can post-transcriptionally regulate genes, are differentially modulated in obesity. A better understanding and identification of such miRNAs could be used as novel therapeutic targets to fight against diseases. In this review, we discuss ways in which ER stress participates as a common molecular process in the pathogenesis of obesity-associated metabolic disorders. Moreover, our review discusses detailed underlying mechanisms through which ER stress and miRNAs contribute to metabolic alteration in adipose tissue in obesity. Hence, identifying mechanistic involvement of miRNAs-ER stress cross-talk in regulating adipose function during obesity could be used as a potential therapeutic approach to combat chronic diseases, including obesity.

7.
Nutrients ; 13(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072678

RESUMO

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases.


Assuntos
Anti-Inflamatórios , Antioxidantes , Produtos Biológicos , Doenças Metabólicas , Animais , Suplementos Nutricionais , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Camundongos , Nanopartículas , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos
8.
Adv Nutr ; 12(5): 2023-2034, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33885739

RESUMO

Obesity is routinely considered as a single disease state, which drives a "one-size-fits-all" approach to treatment. We recently convened the first annual University of North Carolina Interdisciplinary Nutrition Sciences Symposium to discuss the heterogeneity of obesity and the need for translational science to advance understanding of this heterogeneity. The symposium aimed to advance scientific rigor in translational studies from animal to human models with the goal of identifying underlying mechanisms and treatments. In this review, we discuss fundamental gaps in knowledge of the heterogeneity of obesity ranging from cellular to population perspectives. We also advocate approaches to overcoming limitations in the field. Examples include the use of contemporary mouse genetic reference population models such as the Collaborative Cross and Diversity Outbred mice that effectively model human genetic diversity and the use of translational models that integrate -omics and computational approaches from pre-clinical to clinical models of obesity. Finally, we suggest best scientific practices to ensure strong rigor that will allow investigators to delineate the sources of heterogeneity in the population with obesity. Collectively, we propose that it is critical to think of obesity as a heterogeneous disease with complex mechanisms and etiologies, requiring unique prevention and treatment strategies tailored to the individual.


Assuntos
Obesidade , Projetos de Pesquisa , Animais , Humanos , Camundongos
9.
J Nutr Biochem ; 94: 108644, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33838231

RESUMO

Obesogenic and diabetogenic high fat (HF) diets can influence genetic factors in disease development with sexual dimorphic responses. We investigated potential protective effects of tart cherry (TC), fish oil (FO) and TC+FO supplementation in TALLYHO/Jng (TH) and C57BL/6J (B6) mice fed HF diets. Male and female TH and B6 mice were weaned onto five different diets; low fat (LF), HF, and HF supplemented with TC, FO, or TC+FO and maintained. For both males and females on LF, TH mice were heavier and fatter than B6, which was accentuated by HF in males, but not in females. TH males, but not others, developed severe glucose intolerance and hyperglycemia on HF, with reduced mRNA levels of Adipoq and Esr1 in adipose tissue. Considering energy balance, locomotor activity was lower in TH mice than B6 for both sexes without diet effects, except B6 females where HF decreased it. Compared to LF, HF decreased energy expenditure, RER, and food intake (in grams) for both sexes without strain differences. In all mice, but B6 males, HF increased plasma IL6 levels compared to LF. No preventive effects of TC, FO or TC+FO were noted for HF-induced obesity or energy imbalance, but FO alleviated glucose intolerance in TH males. Further, TC and FO decreased plasma IL6 levels, especially in females, without additive or synergistic effects of these two. Collectively, obesogenic and diabetogenic impacts of HF diets differed depending on the genetic predisposition. Moreover, sexually dimorphic effects of dietary supplementation were observed for glucose metabolism and inflammatory markers.


Assuntos
Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica/efeitos adversos , Óleos de Peixe/farmacologia , Obesidade/induzido quimicamente , Prunus avium/química , Adiponectina/genética , Adiponectina/metabolismo , Ração Animal , Animais , Aromatase/genética , Aromatase/metabolismo , Composição Corporal , Gorduras na Dieta/efeitos adversos , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Frutas , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/sangue , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Fatores Sexuais
10.
Biochem J ; 478(7): 1359-1375, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33861844

RESUMO

Atherosclerosis is a chronic inflammatory disease associated with lipid metabolism disorder. Autophagy is a catabolic process and contributes to maintaining cellular homeostasis. Substantial evidence suggests that defective autophagy is implicated in several diseases, including atherosclerosis, while increased autophagy mitigates atherosclerosis development. Thus, understanding the mechanisms of autophagy regulation and its association with atherosclerosis is vital to develop new therapies against atherosclerosis. Dietary bioactive compounds are non-nutrient natural compounds that include phenolics, flavonoids, and carotenoids. Importantly, these bioactive compounds possess anti-inflammatory, antioxidant, and antibacterial properties that may alleviate various chronic diseases. Recently, examining the effects of bioactive compounds on autophagy activity in atherogenesis has drawn considerable attention. The current review discusses the role of macrophage autophagy in the development and progression of atherosclerosis. We also summarize our current knowledge of the therapeutic potential of bioactive compounds on atherosclerosis and autophagy.


Assuntos
Aterosclerose/tratamento farmacológico , Autofagia , Produtos Biológicos/farmacologia , Macrófagos/patologia , Animais , Aterosclerose/patologia , Humanos
11.
Biomedicines ; 9(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800470

RESUMO

Diabetes mellitus (DM) is a complex metabolic disease affecting one-third of the United States population. It is characterized by hyperglycemia, where the hormone insulin is either not produced sufficiently or where there is a resistance to insulin. Patients with Type 1 DM (T1DM), in which the insulin-producing beta cells are destroyed by autoimmune mechanisms, have a significantly increased risk of developing life-threatening cardiovascular complications, even when exogenous insulin is administered. In fact, due to various factors such as limited blood glucose measurements and timing of insulin administration, only 37% of T1DM adults achieve normoglycemia. Furthermore, T1DM patients do not produce C-peptide, a cleavage product from insulin processing. C-peptide has potential therapeutic effects in vitro and in vivo on many complications of T1DM, such as peripheral neuropathy, atherosclerosis, and inflammation. Thus, delivery of C-peptide in conjunction with insulin through a pump, pancreatic islet transplantation, or genetically engineered Sertoli cells (an immune privileged cell type) may ameliorate many of the cardiovascular and vascular complications afflicting T1DM patients.

12.
J Control Release ; 333: 339-351, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33766692

RESUMO

Enhancing thermogenic energy expenditure via promoting the browning of white adipose tissue (WAT) is a potential therapeutic strategy to manage energy imbalance and the consequent comorbidities associated with excess body weight. Adverse effects and toxicities of currently available methods to induce browning of WAT have retarded exploration of this promising therapeutic approach. Targeted delivery of browning agents to adipose stromal cells (ASCs) in subcutaneous WAT to induce differentiation into beige adipocytes may overcome these barriers. Herein, we report for the first time, ASC-targeted delivery of trans-resveratrol (R), a representative agent, using ligand-coated R-encapsulated nanoparticles (L-Rnano) that selectively bind to glycanation site-deficient decorin receptors on ASCs. After biweekly intravenous administration of L-Rnano to obese C57BL/6 J mice for 5 weeks targeted R delivery significantly induced ASCs differentiation into beige adipocytes, which subsequently resulted in 40% decrease in fat mass, accompanied by improved glucose homeostasis and decreased inflammation. Our results suggest that the ASC-targeted nanoparticle delivery of browning agents could be a transformative technology in combating obesity and its comorbidities with high efficacy and low toxicity.


Assuntos
Nanopartículas , Termogênese , Tecido Adiposo Branco , Animais , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Resveratrol , Células Estromais
13.
Mol Cell Endocrinol ; 528: 111245, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33753205

RESUMO

The Renin-Angiotensin System (RAS) is classically recognized for regulating blood pressure and fluid balance. Recently, this role has extended to other areas including inflammation, obesity, diabetes, as well as breast cancer. RAS components are expressed in normal and cancerous breast tissues, and downregulation of RAS inhibits metastasis, proliferation, angiogenesis, and desmoplasia in the tumor microenvironment. Therefore, RAS inhibitors (Angiotensin receptor blockers, ARBs, or angiotensin converting enzyme inhibitors, ACE-I) may be beneficial as preventive adjuvant therapies to thwart breast cancer development and improve outcomes, respectively. Given the beneficial effects of RAS inhibitors in metabolic diseases, which often co-exist in breast cancer patients, combining RAS inhibitors with other breast cancer therapies may enhance the effectiveness of current treatments. This review scrutinizes above associations, to advance our understanding of the role of RAS in breast cancer and its potential for repurposing of RAS inhibitors to improve the therapeutic approach for breast cancer patients.

14.
Biochim Biophys Acta Mol Basis Dis ; 1867(5): 166087, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513428

RESUMO

SLC6A14 is a Na+/Cl--coupled transporter for neutral/cationic amino acids, expressed in ileum and colon. A single-nucleotide polymorphism (SNP), rs2011162 (-22,510C > G), in SLC6A14 coding for the 3'-untranslated region (3'-UTR) is associated with obesity in humans. But the impact of this polymorphism on the transporter expression and its connection to obesity are not known. Our objective was to address these issues. The impact of rs2011162 (-22,510C > G) on SLC6A14 expression was monitored using a luciferase reporter. The link between Slc6a14 and obesity was investigated in wild type and Slc6a14-/- mice when fed a normal diet or a high-fat diet. The obesity-associated 3'-UTR polymorphism reduced SLC6A14 expression. With a high-fat diet, Slc6a14-/- mice gained more weight than wild type mice. With normal diet, there was no difference between the two genotypes. The gain in body weight with the high-fat diet in Slc6a14-/- mice was accompanied with metabolic syndrome. With the high-fat diet, Slc6a14-/- mice showed increased food intake, developed fatty liver, and altered plasma amino acid profile. The high-fat diet-associated hepatic steatosis in Slc6a14-/- mice showed male preponderance. We conclude that the 3'-UTR SNP in SLC6A14 associated with obesity decreases the expression of SLC6A14 and that the deficiency of SLC6A14 is linked to obesity. This is supported by the findings that Slc6a14-/- mice develop obesity, fatty liver, and metabolic syndrome. This connection is evident only with a high-fat diet. Therefore, dietary/pharmacologic interventions that induce SLC6A14 expression in the intestinal tract might have potential for obesity prevention.1.


Assuntos
Sistemas de Transporte de Aminoácidos/fisiologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/patologia , Síndrome Metabólica/patologia , Obesidade/patologia , Animais , Peso Corporal , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Feminino , Metabolismo dos Lipídeos , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo
15.
Adv Nutr ; 12(1): 102-114, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32761179

RESUMO

The influence of diet on the gut microbiota is an emerging research area with significant impact on human health and disease. However, the effects of beef, the most consumed red meat in the United States, on gut microbial profile are not well studied. Following Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, the objective of this systematic review was to conduct a rigorous and thorough review of the current scientific literature regarding the effects of beef protein and the resulting bioactivity of beef protein and amino acids on the gut microbiota, with the goal of identifying gaps in the literature and guiding future research priorities. Utilizing MEDLINE Complete, PubMed, ScienceDirect, Scopus, and Google Scholar databases, we conducted searches including terms and combinations of the following: animal protein, amino acid, beef, bioactive compounds, diet, health, microbiome, peptide, processed beef, and protein. We identified 131 articles, from which 15 were included in our review. The effects of beef on mouse and rat models were mostly consistent for the bacterial phylum level. Short-term (1-4-wk) beef intakes had little to no effect on microbial profiles in humans. Most studies utilized high beef feeding (240-380 g/d), and no study examined recommended amounts of protein [∼3.71 oz/d (105 g/d) meats, poultry, and eggs, or ∼26 oz/week (737 g/wk) from these food sources] according to US dietary guidelines. Additionally, the majority of animal and human studies with adverse findings examined the impact of beef in the context of a diet high in fat or sugar. In conclusion, an extensive gap exists in the literature regarding beef and the microbiota. More studies are necessary to elucidate the role of the microbiota following the consumption of beef, especially in interaction with other dietary compounds, and how beef preparation, processing, and cooking methods differentially influence the biological effects of beef on human health.


Assuntos
Microbioma Gastrointestinal , Animais , Bovinos , Dieta , Ovos , Humanos , Carne , Camundongos , Prevotella , Ratos
17.
Nutrients ; 12(11)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143330

RESUMO

Chronic low-grade inflammation is a primary characteristic of obesity and can lead to other metabolic complications including insulin resistance and type 2 diabetes (T2D). Several anti-inflammatory dietary bioactives decrease inflammation that accompanies metabolic diseases. We are specifically interested in delta-tocotrienol, (DT3) an isomer of vitamin E, and tart cherry anthocyanins (TCA), both of which possess individual anti-inflammatory properties. We have previously demonstrated that DT3 and TCA, individually, reduced systemic and adipose tissue inflammation in rodent models of obesity. However, whether these compounds have combinatorial effects has not been determined yet. Hence, we hypothesize that a combined treatment of DT3 and TCA will have great effects in reducing inflammation in adipocytes, and that these effects are mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), a major inflammatory transcription factor. We used 3T3-L1 adipocytes and treated them with 1-5 µM doses of DT3 along with tart cherry containing 18-36 µg anthocyanin/mL, to assess effects on inflammation. Neither DT3 nor TCA, nor their combinations had toxic effects on adipocytes. Furthermore, pro-inflammatory markers interleukin-6 (IL-6) and p-65 (subunit of NFkB) were reduced at the protein level in media collected from adipocytes with both individual and combined treatments. Additionally, other downstream targets of NFkB including macrophage inflammatory protein 2 (Mip2), and Cyclooxygenase-2 (Cox2) were also significantly downregulated (p ≤ 0.05) when treated with individual and combined doses of DT3 and TCA with no additional combinatorial effects. In summary, DT3 and TCA individually, are beneficial in reducing inflammation with no additional combinatorial effects.


Assuntos
Adipócitos/patologia , Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Prunus avium/química , Vitamina E/análogos & derivados , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Vitamina E/farmacologia
18.
Diabetes Metab Syndr Obes ; 13: 2843-2853, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884312

RESUMO

Introduction: The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion. Methods: To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors. Results: We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion. Discussion: This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.

20.
Biomolecules ; 10(10)2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32992936

RESUMO

Worldwide rates of Western-diet-induced obesity epidemics are growing dramatically. Being linked with numerous comorbidities and complications, including cardiovascular disease, type 2 diabetes, cancer, chronic inflammation, and osteoarthritis (OA), obesity represents one of the most threatening challenges for modern healthcare. Mouse models are an invaluable tool for investigating the effects of diets and their bioactive components against high fat diet (HFD)-induced obesity and its comorbidities. During recent years, very high fat diets (VHFDs), providing 58-60% kcal fat, have become a popular alternative to more traditional HFDs, providing 40-45% total kcal fat, due to the faster induction of obesity and stronger metabolic responses. This project aims to investigate if the 60% fat VHFD is suitable to evaluate the protective effects of curcumin in diet-induced obesity and osteoarthritis. B6 male mice, prone to diet-induced metabolic dysfunction, were supplemented with VHFD without or with curcumin for 13 weeks. Under these experimental conditions, feeding mice a VHFD for 13 weeks did not result in expected robust manifestations of the targeted pathophysiologic conditions. Supplementing the diet with curcumin, in turn, protected the animals against obesity without significant changes in white adipocyte size, glucose clearance, and knee cartilage integrity. Additional research is needed to optimize diet composition, curcumin dosage, and duration of dietary interventions to establish the VHFD-induced obesity for evaluating the effects of curcumin on metabolic dysfunctions related to obesity and osteoarthritis.


Assuntos
Curcumina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Adipócitos/efeitos dos fármacos , Animais , Gorduras na Dieta , Modelos Animais de Doenças , Humanos , Camundongos , Obesidade/etiologia , Obesidade/patologia , Osteoartrite/etiologia , Osteoartrite/patologia
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