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Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

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World Journal of Hepatology 2015年第8期7卷 1012-1019页

作者： Vanessa Souza-mello Biomedical Centre Institute of BiologyDepartment of AnatomyState University of Rio de Janeiro

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

关键词： Peroxisome proliferator-activated receptors Non-alcoholic fatty liver disease Obesity Treatment Insulin resistance Beta-oxidation Lipogenesis

Hepatic structural enhancement and insulin resistance amelioration due to AT1 receptor blockade

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World Journal of Hepatology 2017年第2期9卷 74-79页

作者： Vanessa Souza-mello Biomedical Centre Institute of BiologyDepartment of AnatomyState University of Rio de Janeiro20551-030Brazil

Over the last decade, the role of renin-angiotensin system (RAS) on the development of obesity and its comorbidities has been extensively addressed. Both circulating and local RAS components are up-regulated in obesity and involved in non-alcoholic fatty liver disease onset. Pharmacological manipulations of RAS are viable strategies to tackle metabolic impairments caused by the excessive body fat mass. Renin inhibitors rescue insulin resistance, but do not have marked effects on hepatic steatosis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) yield beneficial hepatic remodeling. ARBs elicit body mass loss and normalize insulin levels, tackling insulin resistance. Also, this drug class increases adiponectin levels, besides countering interleukin-6, tumoral necrosis factor-alpha, and transforming growth factor-beta 1. The latter is essential to prevent from liver fibrosis. When conjugated with peroxisome proliferator-activated receptor (PPAR)-alpha activation, ARB fully rescues fatty liver. These effects might be orchestrated by an indirect up-regulation of MAS receptor due to angiotensin II receptor type 1 (AT1R) blockade. These associations of ARB with PPAR activation and ACE2-angiotensin (ANG) (1-7)-MAS receptor axis deserve a better understanding. This editorial provides a brief overview of the current knowledge regarding AT1R blockade effects on sensitivity to insulin and hepatic structural alterations as well as the intersections of AT1R blockade with peroxisome proliferator-activated receptor activation and ACE2-ANG (1-7) - MAS receptor axis.

关键词： Non-alcoholic fatty liver disease Insulin resistance Angiotensin receptor blockers MAS receptor Renin-angiotensin system

Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

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World Journal of Gastroenterology 2005年第8期11卷 1122-1130页

作者： Elisabetta Ceni Tommaso mello Mirko Tarocchi David W Crabb Anna Caldini Pietro Invernizzi Calogero Surrenti Stefano Milani Andrea Galli Gastroenterology Unit Farmacogenomic Foundation FioiGen Departments of Medicine and of Biochemistry and Molecular Biology Clinical Chemistry Laboratories Department of Medicine Ospedale San Paolo

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

关键词： Thiazolidinediones Pancreatic cancer PPARγ Cancer growth Differentiation

A mutation in the ZNF687 gene that is responsible for the severe form of Paget's disease of bone causes severely altered bone remodeling and promotes hepatocellular carcinoma onset in a knock-in mouse model

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Bone Research 2023年第1期11卷 201-214页

作者： Sharon Russo Federica Scotto di Carlo Antonio Maurizi Giorgio Fortunato Anna Teti Danilo Licastro Carmine Settembre Tommaso mello Fernando Gianfrancesco Institute of Genetics and Biophysics“Adriano Buzzati-Traverso” National Research Council of ItalyNaplesItaly Department of Environmental Biological and Pharmaceutical Sciences and Technologies(DiSTABiF)University of Campania Luigi VanvitelliCasertaItaly Department of Biotechnological and Applied Clinical Sciences University of L’AquilaL’AquilaItaly AREA Science Park PadricianoTriesteItaly Telethon Institute of Genetics and Medicine(TIGEM) PozzuoliItaly Gastroenterology Unit Department of Experimental and Clinical Biochemical Sciences“Mario Serio”University of FlorenceFlorenceItaly IRCCS INM Neuromed PozzilliISItaly

Paget’s disease(PDB)is a late-onset bone remodeling disorder with a broad spectrum of symptoms and *** of the most aggressive forms is caused by the P937R mutation in the ZNF687 *** the genetic involvement of ZNF687 in PDB has been extensively studied,the molecular mechanisms underlying this association remain ***,we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype,resulting in severely altered bone *** microcomputed tomography analysis,we observed that 8-month-old mutant mice showed a mainly osteolytic phase,with a significant decrease in the trabecular bone volume affecting the femurs and the ***,osteoblast activity was deregulated,producing disorganized ***,this phenotype became pervasive in 16-month-old mice,where osteoblast function overtook bone resorption,as highlighted by the presence of woven bone in histological analyses,consistent with the PDB ***,we detected osteophytes and intervertebral disc degeneration,outlining for the first time the link between osteoarthritis and PDB in a PDB mouse *** sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687,e.g.,Tspan7,Cpe,Vegfc,and Ggt1,confirming its role in this ***,in this mouse model,the mutation was also associated with a high penetrance of hepatocellular ***,this study established an essential role of Zfp687 in the regulation of bone remodeling,offering the potential to therapeutically treat PDB,and underlines the oncogenic potential of ZNF687.

关键词： RAW264.7 Paget remodeling

Theory of Capital,Investment and Exchange Rate:A New Developmentalist Equation

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Chinese Business Review 2017年第4期16卷 159-169页

作者： Cristina Helena Pintode mello ESPM-SP Sao PauloBrazil

The article deals with the relationship between the decision to invest and the exchange rate. The literature relates investment at interest rate. An increase in the interest rate would reduce the investment expenditure. Jorgenson’s equation uses the flexible accelerator model, taxation, and the cost of capital to explain and predict the amount of investment in machinery and equipment. The relationship between the exchange rate and the investment appears in the literature as a direct relation. An appreciated exchange rate allows the importation of cheaper machinery and equipment and increases productive investments. This paper proposes a modified equation in which the appreciated exchange rate inhibits productive investments by reducing the expectation of profit, either because the domestic market becomes more competitive or because exports decrease. It still incorporates in the model of Jorgenson the idea that the unit cost of labor is the relevant variable to explain the choice of investing, assuming a function of production of fixed coefficients.

关键词： investment exchange rate economic development decision expectation profit

Effects of Soluble Silicate and Nanosilica Application on Rice Nutrition in an Oxisol

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Pedosphere 2018年第4期28卷 597-606页

作者： Rita de Cassia FELIX ALVAREZ Renato de mello PRADO Guilherme FELISBERTO Angelica Cristina FERNANDES DEUS Raimundo Leonardo LIMA DE OLIVEIRA Federal University of Mato Grosso do Sul Chapadao do Sul 79560-000 (Brazil) University of the State of Sao Paulo UNESP School of Agronomic Sciences Department of Soils and Fertilizers Jaboticabal 14884-900 (Brazil)

Silicon （Si） has been supplied to plants via application of calcium silicate to soil; however, high doses of calcium silicate are required because of its low solubility. Nanoparticles can reduce Si doses and be applied to seeding furrows. This study investigated the effects of liquid Si sources, i.e., highly soluble silicate （115.2 g L^-1 Si and 60.5 g L^-1 Na20） and nanosilica （〈 200 nm）, on Si uptake by rice plants, plant lignification, plant C：N：P stoichiometry, plant physiology, and grain yield using an Oxisol under greanhouse condistions. The treatments included the application of nanosilica and soluble silicate to seeding furrows at Si doses of 0, 605, 1210, and 2 420 g ha^-1. Plant uptake and treatment effects were evaluated by measuring C and lignin contents, Si, N, and P accumulation, physiological characteristics, and grain yield of rice. The deposition of silica bodies and amorphous silica in the flag leaves was analyzed using scanning electron microscopy. Application of liquid Si increased Si accumulation in rice by 47.3% in relation to the control （0 g ha^-1 Si）, regardless of the Si sources used. Nanosilica application increased leaf lignin content by 112.7% when compared to that in the control. Silicon moderately affected the net C assimilation （increased by 1.83%） and transpiration rates （increased by 48.3%）; however, Si influenced neither plant growth nor grain yield of rice. These results are explained by the lack of biotic or abiotic stress in rice plants during the experiment. To the best of our knowledge, in Brazilian agriculture, this is the first report on the use of nanosilica as a Si fertilizer and its effect on plant nutrition. This study provides evidence that rice plants absorb and accumulate nanoparticles; however, further studies are required to investigate the use of nanoparticles in other plant species.

关键词： C:N:P stoichiometry grain yield leaf lignin net C assimilation plant physiology silicon source

Recommendations for Using Wiki in Online Group Projects in Engineering Education

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Chinese Business Review 2016年第3期15卷 132-142页

作者： Glaucia Nolasco de Almeida mello Pontifical Catholic University of Minas Gerais Belo Horizonte Brazil

Although Web 2.0 tools like blogs and wikis have been used for supporting collaborative learning in higher education, there are not many reports about implementation of that resource on engineering in Brazil. In this way, the main purpose of this research is to use a wiki platform for online activities and evaluate how students collaborate with each other in online tasks. It was investigated how collaboration can be measured on wiki platform During four-week online activities, 40 students of Civil Engineering course were monitored on Wikispaces~ platform. All students＇ actions were analyzed and classified as low, medium, or high level of collaboration. The data were collected through the statistical reports of Wikispaces~ and Google Analytics platforms. It computed 336 students＇ actions： 16.67% as high level, 45.24% as medium, and 38.10% as low. During informal interview, most of students （70%） related that wiki was a nice tool for collaboration work. The results indicated that wiki platform is an important way to develop innovative activities and tasks for the purpose of improving engineers＇ abilities and skills such as： writing communication, organization, collaboration, and critical thinking development.

关键词： wikis and higher education wiki-based project collaborative activities online measuring collaborationonline

Decontamination of mobile phones and electronic devices for health care professionals using a chlorhexidine/carbomer 940■gel

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Frontiers of Chemical Science and Engineering 2019年第1期13卷 192-198页

作者： Rafael Muniz de Oliveira Nereida mello da Rosa Gioppo Jancineide Oliveirade Carvalho Francilio Carvalho Oliveira Thomas Jay Webster Fernanda Roberta Marciano Anderson Oliveira Lobo University Hospital of the West of Parana State University of West of Parana Cascavel PR Brazil University Center for Health. Humanities and Technology of Piaui (UNINOVAFAPI). Piaui Brazil Science and Technology Institute Brasil University Itaquera SP Brazil Nanomedicine Laboratory Department of Chemical Engineering Northeastern University MA 02115 USA Materials Science and Engineering graduation program Technology Center Federal University of Piaui. PI Brazil

Though they reduce microorganism growth, current hospital disinfectants also damage many of today’s modern electronic devices such as tablets and smartphones. Herein, the efficacy of a new chlorhexidine digluconate gel (CDG) was tested as a disinfectant for mobile and electronic devices in a clinical environment. Specifically, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus were used to infect the screen of eight smartphones. The CDG was prepared at concentrations of 2%, 4% and 6%, and tested on paper disks infected with these bacteria before being tested on the smartphones. The devices were disinfected with the CDG gel (4%) at two times: immediately and after 5 min of the bacterial contamination. In all cases, the CDG gel eliminated 100% of gram-positive and gram-negative microorganisms compared to the control (without any agent). In addition, the gel did not damage the smartphones. Therefore, our study suggests that the CDG gel may be applied to disinfect a wide range of electronic devices for health care professionals in the hospital environment.

关键词： smartphones disinfection clinical environment chlorhexidine bacteria

Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

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World Journal of Gastroenterology 2013年第38期19卷 6383-6397页

作者： Michael Luis Ana Tavares Liliana S Carvalho Lúcio Lara-Santos António Araújo Ramon Andrade de mello Gastrointestinal Unit Service of Medical OncologyPortuguese Oncology Institute4200-072 PortoPortugal Gastrointestinal Unit Experimental Pathology and Therapeutics GroupResearch Center-Portuguese Oncology Institute4200-072 PortoPortugal Department of Pharmacology and Therapeutics Faculty of MedicineUniversity of Porto4200-319 PortoPortugal Institute of Cellular and Molecular Biology 4150-180 PortoPortugal Gastrointestinal Unit Section of Surgical OncologyPortuguese Oncology Institute4200-072 PortoPortugal Department of Medicine Faculty of MedicineUniversity of Porto4200-319 PortoPortugal

Globally,gastric cancer is the 4thmost frequently diagnosed cancer and the 2ndleading cause of death from cancer,with an estimated 990000 new cases and738000 deaths registered in *** the advanced setting,standard chemotherapies protocols acquired an important role since last decades in prolong ***,recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2(HER2)***,an anti-HER2 monoclonal antibody,was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based ***,HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this ***,we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer,providing a comprehensive overview of molecular mechanisms and novel trials involved.

关键词： Gastric cancer Human epidermal growth factor receptor 2 Biomarkers Target therapies Trastuzumab Lapatinib Pertuzumab Trastuzumab-DM1 Afatinib