Publications by authors named "Ana P Gomes"

43 Publications

Age-induced metabolic reprogramming underlies cancer progression.

Mol Cell Oncol 2021 3;8(2):1876506. Epub 2021 Feb 3.

Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Aging is a main risk factor for cancer. Using human serum we demonstrated that tumor progression and metastases occur, at least in part, as a manifestation of global metabolic deregulation of the aged host. This shows that the role of aging in cancer goes far beyond increased exposure time to mutagens; the aging process coordinates various aspects required for malignancy.
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http://dx.doi.org/10.1080/23723556.2021.1876506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018342PMC
February 2021

Comparison of the effectiveness of single- and multiple-sessions disinfection protocols against endotoxins in root canal infections: systematic review and meta-analysis.

Sci Rep 2021 Jan 13;11(1):1226. Epub 2021 Jan 13.

Endodontic Division, Department of Advanced Oral Sciences and Therapeutics, School of Dentistry, University of Maryland, Baltimore, MD, USA.

This systematic review (SR) addressed the following common clinical question: What is more effective in reducing or eliminating endotoxin in endodontic infections-single or multiple-session treatments using calcium hydroxide medications? Literature searches of Medline/PubMed, Embase, Cochrane Library, Scielo, Science Direct, Web of Knowledge, Scopus, and Google Scholar databases. Two reviewers independently assessed the eligibility for inclusion, extracted data, and evaluated the quality of the studies using the risk of bias tools. Electronic searches resulted in 358 articles, of which 32 studies were included for full-text assessment, and nine were included in this review. Meta-analysis pooling all the nine studies revealed lower levels of endotoxin for multiple-session treatment (P < 0.001). The sub-group analysis indicated no difference between single-session and 7 days of Ca(OH) medication (SMD - 0.32; P = 0.22). However, 14-days (I = 80.5%, P < 0.001) and 30-days (I = 78.9%, P < 0.01) of Ca(OH) medication was more effective than single-session treatment (both, p < 0.001). Overall, Overall, this SR provides evidence to support that multiple-session disinfection protocols with the placement of Ca(OH) medications are more effective in reducing the levels of endotoxin from root canal infections compared to single-session when applied for 14 and 30 days.
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http://dx.doi.org/10.1038/s41598-020-79300-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806761PMC
January 2021

Impact of COVID-19 Pandemic on Cancer Research.

Cancer Cell 2020 11 8;38(5):591-593. Epub 2020 Oct 8.

The COVID-19 pandemic is profoundly changing cancer researchers and cancer research. Leaders from different fields and at different career stages share their perspectives.
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http://dx.doi.org/10.1016/j.ccell.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543995PMC
November 2020

Age-induced accumulation of methylmalonic acid promotes tumour progression.

Nature 2020 09 19;585(7824):283-287. Epub 2020 Aug 19.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.
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http://dx.doi.org/10.1038/s41586-020-2630-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785256PMC
September 2020

Targeting the premetastatic niche: epigenetic therapies in the spotlight.

Signal Transduct Target Ther 2020 05 11;5(1):68. Epub 2020 May 11.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41392-020-0165-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211564PMC
May 2020

Histone H3 variants at the root of metastasis.

Mol Cell Oncol 2020 10;7(2):1684128. Epub 2020 Jan 10.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

Chromatin remodeling is at the root of any cell fate decision, laying the foundation for the necessary reprogramming to occur. Our work shows histone H3 variants as a new addition to the ever-growing body of epigenetic regulators, one that is essential for cell fate transitions in carcinoma cells to promote tumor progression and metastasis.
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http://dx.doi.org/10.1080/23723556.2019.1684128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051143PMC
January 2020

Dynamic Incorporation of Histone H3 Variants into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization.

Cancer Cell 2019 10 26;36(4):402-417.e13. Epub 2019 Sep 26.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address:

Metastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation. Here, we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin, triggering deposition of H3.3 variant at the promoters of poor-prognosis genes and metastasis-inducing transcription factors. This specific incorporation of H3.3 into chromatin is both necessary and sufficient for the induction of aggressive traits that allow for metastasis formation. Together, our data clearly show incorporation of histone variant H3.3 into chromatin as a major regulator of cell fate during tumorigenesis, and histone chaperones as valuable therapeutic targets for invasive carcinomas.
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http://dx.doi.org/10.1016/j.ccell.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801101PMC
October 2019

Beyond the Warburg Effect: How Do Cancer Cells Regulate One-Carbon Metabolism?

Front Cell Dev Biol 2018 15;6:90. Epub 2018 Aug 15.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States.

Altered metabolism in cancer cells is critical for tumor growth. One of the most notable aspects of this metabolic reprogramming lies in one-carbon metabolism. Cells require one-carbon units for nucleotide synthesis, methylation reactions, and for the generation of reducing cofactors. Therefore, the ability to rewire and fine-tune one-carbon metabolism is essential for the maintenance of cellular homeostasis. In this review, we describe how the major nutrient, energy, and redox sensors of the cell play a significant role in the regulation of flux through one-carbon metabolism to enable cell fate decisions. We will also discuss how dysregulated oncogenic signaling hijacks these regulatory mechanisms to support and sustain high rates of proliferation and cell survival essential for tumor growth.
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http://dx.doi.org/10.3389/fcell.2018.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103474PMC
August 2018

mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-Dependent Foxk1 Phosphorylation.

Mol Cell 2018 06 31;70(5):949-960.e4. Epub 2018 May 31.

Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea. Electronic address:

The mammalian Target of Rapamycin Complex 1 (mTORC1)-signaling system plays a critical role in the maintenance of cellular homeostasis by sensing and integrating multiple extracellular and intracellular cues. Therefore, uncovering the effectors of mTORC1 signaling is pivotal to understanding its pathophysiological effects. Here we report that the transcription factor forkhead/winged helix family k1 (Foxk1) is a mediator of mTORC1-regulated gene expression. Surprisingly, Foxk1 phosphorylation is increased upon mTORC1 suppression, which elicits a 14-3-3 interaction, a reduction of DNA binding, and nuclear exclusion. Mechanistically, this occurs by mTORC1-dependent suppression of nuclear signaling by the Foxk1 kinase, Gsk3. This pathway then regulates the expression of multiple genes associated with glycolysis and downstream anabolic pathways directly modulated by Foxk1 and/or by Foxk1-regulated expression of Hif-1α. Thus, Foxk1 mediates mTORC1-driven metabolic rewiring, and it is likely to be critical for metabolic diseases where improper mTORC1 signaling plays an important role.
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http://dx.doi.org/10.1016/j.molcel.2018.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591025PMC
June 2018

Effects of Resistance Training on Cardiovascular Function in Patients With Peripheral Artery Disease: A Randomized Controlled Trial.

J Strength Cond Res 2018 Apr;32(4):1072-1080

Hospital Israelita Albert Einstein, São Paulo-SP, Brazil.

Gomes, APF, Correia, MA, Soares, AHG, Cucato, GG, Lima, AHRA, Cavalcante, BR, Sobral-Filho, DC, and Ritti-Dias, RM. Effects of resistance training on cardiovascular function in patients with peripheral artery disease: A randomized controlled trial. J Strength Cond Res 32(4): 1072-1080, 2018-The aim of this study was to analyze the effects of resistance training on cardiovascular function of patients with peripheral artery disease (PAD). In total, 30 patients with PAD were invited to participate in this randomized controlled trial, randomly allocated to a control (n = 15, 66 ± 2 years; stretching and relaxation exercises) or resistance training group (n = 15, 60 ± 3 years; 3 sets of 10 repetitions of 8 whole-body exercises, with a 2-minute interval between sets). Resting and 24-hour blood pressure (BP), cardiac output, systemic vascular resistance, and autonomic variables were obtained before and after 12 weeks of intervention. A blinded investigator performed all analyses. After 12 weeks of intervention there was maintenance of resting systolic, diastolic, and mean BP (p > 0.18), cardiac output (p = 0.46), and systemic vascular resistance (p = 0.55) in both groups. There was a time effect reduction in heart rate (p = 0.02), accompanied by changes in cardiac autonomic modulation (p = 0.03). There were no changes in 24-hour systolic, diastolic, and mean BP, heart rate, or rate pressure product (p > 0.05). The BP variability decreased in systolic (asleep, p = 0.003), diastolic (24 hours and awake, p = 0.001), and mean (24 hours and asleep, p < 0.02) only in the resistance training (RT) group. Twelve weeks of RT did not change resting and 24-hour BP, or their hemodynamic and autonomic determinants in patients with PAD; however, there were decreases in BP variability, indicating that it could be considered as an alternative to reducing cardiovascular risk in patients with PAD.
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http://dx.doi.org/10.1519/JSC.0000000000001914DOI Listing
April 2018

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization.

Cancer Cell 2018 03;33(3):347-354

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Electronic address:

Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.
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http://dx.doi.org/10.1016/j.ccell.2018.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889305PMC
March 2018

Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance.

Mol Metab 2018 01 6;7:1-11. Epub 2017 Nov 6.

Sanford-Burnham-Prebys Medical Discovery Institute, Orlando, FL, USA; Pennington Biomedical Research Center, Baton Rouge, LA, USA; Translational Research Institute for Metabolism and Diabetes, Orlando, FL, USA. Electronic address:

Objective: Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD), an essential co-substrate regulating a myriad of signaling pathways. We produced a mouse that overexpressed NAMPT in skeletal muscle (NamptTg) and hypothesized that NamptTg mice would have increased oxidative capacity, endurance performance, and mitochondrial gene expression, and would be rescued from metabolic abnormalities that developed with high fat diet (HFD) feeding.

Methods: Insulin sensitivity (hyperinsulinemic-euglycemic clamp) was assessed in NamptTg and WT mice fed very high fat diet (VHFD, 60% by kcal) or chow diet (CD). The aerobic capacity (VOmax) and endurance performance of NamptTg and WT mice before and after 7 weeks of voluntary exercise training (running wheel in home cage) or sedentary conditions (no running wheel) were measured. Skeletal muscle mitochondrial gene expression was also measured in exercised and sedentary mice and in mice fed HFD (45% by kcal) or low fat diet (LFD, 10% by kcal).

Results: NAMPT enzyme activity in skeletal muscle was 7-fold higher in NamptTg mice versus WT mice. There was a concomitant 1.6-fold elevation of skeletal muscle NAD. NamptTg mice fed VHFD were partially protected against body weight gain, but not against insulin resistance. Notably, voluntary exercise training elicited a 3-fold higher exercise endurance in NamptTg versus WT mice. Mitochondrial gene expression was higher in NamptTg mice compared to WT mice, especially when fed HFD. Mitochondrial gene expression was higher in exercised NamptTg mice than in sedentary WT mice.

Conclusions: Our studies have unveiled a fascinating interaction between elevated NAMPT activity in skeletal muscle and voluntary exercise that was manifest as a striking improvement in exercise endurance.
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http://dx.doi.org/10.1016/j.molmet.2017.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784330PMC
January 2018

Adding Polyamine Metabolism to the mTORC1 Toolkit in Cell Growth and Cancer.

Dev Cell 2017 07;42(2):112-114

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Electronic address:

The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a major nutrient sensor and regulator of cellular metabolic flux. Reporting recently in Nature, Zabala-Letona et al. (2017) show that mTORC1 regulates an additional branch of metabolism in the cell-polyamine synthesis-that is important for prostate cancer tumorigenicity.
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http://dx.doi.org/10.1016/j.devcel.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705022PMC
July 2017

Does supplemental photodynamic therapy optimize the disinfection of bacteria and endotoxins in one-visit and two-visit root canal therapy? A randomized clinical trial.

Photodiagnosis Photodyn Ther 2017 Sep 12;19:205-211. Epub 2017 Jun 12.

Department of Restorative Dentistry, Endodontic Division, São José dos Campos Dental School, State University of São Paulo, UNESP, Brazil; University of Maryland-Baltimore, Department Oral Sciences & Therapeutics, School of Dentistry, Baltimore, Maryland 21201. Electronic address:

Aim: To evaluate the effectiveness of supplemental photodynamic therapy (PDT) in optimizing the removal of bacteria and endotoxins from primarily infected root canals after one-visit and two-visit treatments.

Methodology: Twenty-four primarily infected root canals with apical periodontitis were selected and randomly divided into one-visit (n=12) and two-visit treatment groups (n=12). Chemo-mechanical preparation (CMP) was performed by using the single-file reciprocating technique+2.5% NaOCL and a final rinse with 17% EDTA. The photosensitizer agent (methylene blue 0.1mg/mL) was applied to root canals for 60s before application of laser with a potency of 60mW and energy density of 129J/cm for 120s after CMP in the one-visit treatment and after 14-day inter-appointment medication with Ca(OH)+Saline solution (SSL) in the two-visit treatment. Samples were collected before and after root canal procedures. Endotoxins were quantified by chromogenic limulus amebocyte lysate assay. Culture techniques were used to determine bacterial colony-forming unit counts.

Results: Bacteria and endotoxins were detected in 100% of the initial samples, with median values of 1.97×10 CFU/mL and 24.983EU/mL, respectively. The CMP using single-file reciprocating technique was effective in the reduction of bacteria and endotoxins (All, p<0.05). The supplemental PDT was effective in reducing bacterial load in the one-visit (p<0.05) but not in the two-visit treatment after use of Ca(OH) medication for 14days (p>0.05). In the two-visit group, after 14days of inter-appointment medication with Ca(OH), a significant reduction in the median levels of endotoxins was found in comparison to CMP alone (from 1.041 to 0.094EU/mL) (p<0.05). Despite the type of treatment, the supplemental PDT was not effective against endotoxins (p>0.05).

Conclusions: The photodynamic therapy optimized the disinfection of bacteria from root canals in one-visit but not for two visit treatment modality with the accomplishment of calcium hydroxide medication. Despite the type of treatment, the supplemental PDT was not effective against endotoxins.
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http://dx.doi.org/10.1016/j.pdpdt.2017.06.005DOI Listing
September 2017

Clinical comparison of the effectiveness of 7- and 14-day intracanal medications in root canal disinfection and inflammatory cytokines.

Clin Oral Investig 2018 01 6;22(1):523-530. Epub 2017 Jun 6.

Department of Semiology, School of Dentistry, Federal University of Pelotas, Pelotas, RS, Brazil.

Objective: This clinical study compared the effectiveness of 7- and 14-day intracanal medications in the reduction of bacteria/endotoxins from primarily infected root canals and determined their antigenicity against macrophages through the levels of cytokines.

Methods: Seventy-two primarily infected teeth were randomly divided into six groups according to medication and time of application: 7-day groups = G1, Ca(OH) + saline solution (SSL); G2, Ca(OH) + 2% chlorhexidine (CHX) gel; and G3, 2% CHX gel and 14-day groups = G4, Ca(OH) + SSL; G5, Ca(OH) + 2% CHX gel; and G6, 2% CHX gel (all groups, n = 12). Bacterial and endotoxin samples were collected from root canals and inflammatory cytokines of macrophages supernatants. Culture techniques were used to determine bacterial counts and limulus amebocyte lysate (LAL) assay to quantify endotoxins. IL-1β, TNF-α, and PGE were measured by ELISA-assay.

Results: With regard to the bacterial reduction, no differences were found between all protocols tested (p > 0.05). The CHX protocols (G3 and G6) exhibited the lowest effectiveness against endotoxins (p < 0.05). All protocols were effective in lowering the levels of IL-1β, TNF-α, and PGE (p < 0.05), with no difference between the medications tested on days 7 or 14 (p > 0.05). Particularly, the 7-day CHX-protocol (G3) exhibited the lowest effectiveness in lowering the levels of most cytokines compared to the 14-day protocols (G6) (p < 0.05).

Conclusions: All the 7- and 14-day intracanal medications were effective in reducing bacteria and endotoxins as well as in lowering the levels of inflammatory cytokines, with CHX showing limited effectiveness against endotoxins. Moreover, 7-day CHX-protocol exhibited the lowest effectiveness in lowering the levels of most cytokines compared to the 14-day protocols.

Clinical Significance: Seven-day CHX protocol is the less effective protocol and should be carefully applied by the clinician.
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http://dx.doi.org/10.1007/s00784-017-2143-xDOI Listing
January 2018

Oral and Maxillofacial Lesions Diagnosed in Older People of a Brazilian Population: A Multicentric Study.

J Am Geriatr Soc 2017 Jul 13;65(7):1586-1590. Epub 2017 Mar 13.

Postgraduate Program in Oral Pathology, UFRN, Natal, Brazil.

Objectives: The aim of this study was to investigate the prevalence of oral and maxillofacial lesions among older adults (≥60 years) from representative regions in Brazil.

Design: Retrospective descriptive cross-sectional study.

Setting: Biopsy records were obtained from the archives of four Brazilian referral centers of oral diagnosis between 2000 and 2016.

Participants: A total of 45,506 biopsy records of all patients were analyzed, of these 7,259 persons aged 60 and older were selected.

Measurements: Data such as gender, age, race, anatomical location, and histopathological diagnosis were collected and categorized. Pearson's chi-square test (P < .005) was used to evaluate differences in the frequency of the several groups of oral lesions.

Results: Oral and maxillofacial lesions were diagnosed in 7,259 older people, including 59.4% women (P < .001) and 61.3% white patients (P = .07). The most commonly affected sites were the cheek mucosa (20.3%) and mandible (8.9%) (P < .001). Reactive and inflammatory lesions were the most common lesions, followed by neoplasms. Oral squamous cell carcinoma was the most prevalent neoplasm (83.4%) (P < .001).

Conclusion: Knowledge of oral diseases obtained from biopsy records provides more accurate data about the diagnosis and oral health of elderly patients. These indicators thus support the development of specific health policies for the prevention and treatment of oral and maxillofacial lesions that affect this population.
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http://dx.doi.org/10.1111/jgs.14815DOI Listing
July 2017

Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver.

Purinergic Signal 2017 06 15;13(2):179-190. Epub 2016 Nov 15.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.

Although adenosine A receptors (A1R) have been associated to ischemic preconditioning (IPC), direct evidence for their ability to preserve mitochondrial function upon hepatic preconditioning is still missing and could represent a novel strategy to boost the quality of liver transplants. We tested if the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prevented IPC in the liver and if the A1R agonist 2-chloro-N-cyclopentyladenosine (CCPA) might afford a pharmacological preconditioning. Livers underwent a 120 min of 70% warm ischemia and 16 h of reperfusion (I/R), and the IPC group underwent a 5-min ischemic episode followed by a 10-min period of reperfusion before I/R. DPCPX or CCPA was administered intraperitoneally 2 h before IPC or I/R. The control of mitochondrial function emerged as the central element affected by IPC and controlled by endogenous A1R activation. Thus, livers from IPC- or CCPA-treated rats displayed an improved oxidative phosphorylation with higher state 3 respiratory rate, higher respiratory control ratio, increased ATP content, and decreased lag phase. IPC and CCPA also prevented the I/R-induced susceptibility to calcium-induced mitochondrial permeability transition, the rate of reactive oxygen species (ROS) generation, and the decreased mitochondrial content of phospho-Ser GSK-3β. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3β activity by Akt-mediated Ser-GSK-3β phosphorylation preserving the efficiency of oxidative phosphorylation and ROS-mediated cell death in the ability of A1R activation to mimic IPC in the liver. In conclusion, the parallel between IPC and A1R-mediated preconditioning also paves the way to consider a putative therapeutic use of the later in liver transplants.
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http://dx.doi.org/10.1007/s11302-016-9548-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432478PMC
June 2017

Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers.

Proc Natl Acad Sci U S A 2016 Feb 1;113(7):1778-83. Epub 2016 Feb 1.

Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism.
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http://dx.doi.org/10.1073/pnas.1521548113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763784PMC
February 2016

A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways.

Curr Opin Biotechnol 2015 Aug 3;34:110-7. Epub 2015 Jan 3.

Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address:

In multicellular organisms, individual cells have evolved to sense external and internal cues in order to maintain cellular homeostasis and survive under different environmental conditions. Cells efficiently adjust their metabolism to reflect the abundance of nutrients, energy and growth factors. The ability to rewire cellular metabolism between anabolic and catabolic processes is crucial for cells to thrive. Thus, cells have developed, through evolution, metabolic networks that are highly plastic and tightly regulated to meet the requirements necessary to maintain cellular homeostasis. The plasticity of these cellular systems is tightly regulated by complex signaling networks that integrate the intracellular and extracellular information. The coordination of signal transduction and metabolic pathways is essential in maintaining a healthy and rapidly responsive cellular state.
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http://dx.doi.org/10.1016/j.copbio.2014.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490161PMC
August 2015

Clinical influence of different intracanal medications on Th1-type and Th2-type cytokine responses in apical periodontitis.

J Endod 2015 Feb 11;41(2):169-75. Epub 2014 Nov 11.

Department of Restorative Dentistry, Endodontic Division, Fluminense Federal University (UFF), Niteroi, Rio de Janeiro, Brazil.

Introduction: This clinical study assessed the influence of different intracanal medications on Th1-type and Th2-type cytokine responses in apical periodontitis and monitored the levels of bacteria from primarily infection during endodontic procedures.

Methods: Thirty primarily infected teeth were randomly divided into 3 groups according to the medication selected: chlorhexidine (CHX), 2% CHX gel; Ca(OH)2/SSL, Ca(OH)2 + SSL; and Ca(OH)2/CHX, Ca(OH)2 + 2% CHX gel (all, n = 10). Bacterial sample was collected from root canals, and the interstitial fluid was sampled from lesions. Culture techniques were used to determine bacterial counts (colony-forming units/mL). Th1 (tumor necrosis factor-α, interferon-γ, and interleukin [IL]-2) and Th2 cytokines (IL-4, IL-5, and IL-13) were measured by enzyme-linked immunosorbent assay.

Results: All intracanal medication protocols were effective in reducing the bacterial load from root canals (all P < .05) and lowering the levels of Th1-type cytokines in apical lesions (all P < .05), with no differences between them (P > .05). Both Ca(OH)2 treatment protocols significantly increased the levels of Th2-type cytokines (P < .05), with no differences between them (P > .05). Thus, chlorhexidine medication showed the lowest effectiveness in increasing the levels of Th2-type cytokine. After treatment, regardless of the type of medication, the linear regression analysis indicated the down-regulation of Th2-type cytokines by Th1-type cytokines.

Conclusions: All intracanal medication protocols were effective in reducing bacterial load and lowering the levels of Th1-type cytokines. Thus, the use of Ca(OH)2 medications contributed to the increase in the Th2-type cytokine response in apical periodontitis.
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http://dx.doi.org/10.1016/j.joen.2014.09.028DOI Listing
February 2015

Endodontic retreatment: clinical comparison of reciprocating systems versus rotary system in disinfecting root canals.

Clin Oral Investig 2015 Jul 21;19(6):1411-7. Epub 2014 Nov 21.

Department of Restorative Dentistry, Endodontics Division-UNESP-UNIV Estadual Paulista, São José dos Campos Dental School, São José dos Campos, São Paulo, Brazil,

Introduction: This clinical study was conducted to compare the effectiveness of single-file reciprocating systems and rotary systems in removing endotoxins and cultivable bacteria in endodontic retreatment.

Methods: Thirty endodontically treated teeth with post-treatment apical periodontitis were selected. The specimens were divided into three groups according to the system used: WaveOne (n = 10), Reciproc instrument (n = 10), and ProTaper Universal Retreatment system (n = 10). Samples were collected before and after chemomechanical preparation. The irrigation was performed by using 2.5% sodium hypochlorite. A chromogenic limulus amebocyte lysate assay test was used to quantify endotoxins. Culture techniques were used to determine bacterial colony-forming unit counts.

Results: At baseline, endotoxins and cultivable bacteria were recovered from 100% of the root canal samples in a median value of 5.84 EU/mL and 4.98 × 10(3) CFU/mL, respectively. After CMP, no differences were found in the median percentage values of endotoxin reduction achieved with reciprocating systems-WaveOne [94.11%] and Reciproc [93.29%] and with rotary systems-ProTaper [94.98%] (P > 0.05). Both single-file reciprocating systems [WaveOne (98.27%) and Reciproc (99.54%)] and rotary system [ProTaper (98.73%)] were effective in reducing bacterial load (P > 0.05). Moreover, no differences were found among the systems tested.

Conclusions: The Reciproc and WaveOne reciprocating systems were as effective as the ProTaper system for removal of endotoxins and bacteria in endodontic retreatment.

Clinical Relevance: All systems tested were effective to remove cultivable bacteria and endotoxin in endodontic retreatment. As no differences among systems were observed, it is possible to suggest that clinicians should choose the preferred technique to perform endodontic.
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http://dx.doi.org/10.1007/s00784-014-1360-9DOI Listing
July 2015

Measuring PGC-1α and its acetylation status in mouse primary myotubes.

Methods Mol Biol 2015 ;1241:49-57

Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.

Metabolic flexibility is vital for the cells to adapt to different energetic situations, allowing the organisms to adapt to changing conditions and survive challenges. One of the most important regulators of the metabolic flexibility is PGC-1α activity. PGC-1α integrates numerous signals and regulates a variety of transcription factors and nuclear receptors that together regulate mitochondrial homeostasis and fatty acid oxidation. One of the major ways that PGC-1α activity is regulated is by changes in its acetylation status. Thus measuring the acetylation status of PGC-1α is an important indicator of the metabolic flexibility of the cells. In this chapter, we describe an approach to evaluate PGC-1α acetylation in primary mouse myotubes. The method is applicable to other cell types and tissues as well.
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http://dx.doi.org/10.1007/978-1-4939-1875-1_5DOI Listing
June 2015

Assessment of the efficacy of the utilisation of conventional and electric toothbrushes by the older adults.

Gerodontology 2020 Sep 17;37(3):297-302. Epub 2014 Jul 17.

Federal University of Espirito Santo, Centro Biomédico, Avenida Marechal Campos, 1468, Maruipe, CEP 29043-900, Vitoeria, ES, Brasil.

Objective:   To evaluate the efficacy of electric and conventional toothbrushes for a group of elderly individuals.

Background:   Although the electric toothbrush has been recommended for elderly individuals, there had previously never been a study regarding its efficacy.

Material And Methods:   Sixty independent elders of both genders with different oral conditions from the Center Adult Day Vitória, Espírito Santo, Brazil, were randomly divided into two groups of 30 individuals. One group received the Oral B CrossAction Power electric toothbrush, whereas the other received a conventional Bitufo Class 32 soft toothbrush to perform oral hygiene. The bacterial plaque index (O'Leary Plaque Index) and DMFT index were assessed as a measure of oral hygiene and oral health. The data were analysed using the Shapiro-Wilk, Mann-Whitney and Wilcoxon tests.

Results:   The results of the efficacy of the Oral B Cross Action Power electric toothbrush demonstrated that on the 7th and 15th days, the bacterial plaque indexes were 24.91 ± 12.81 and 22.11 ± 14.46, respectively, which corresponds to a 50.24% removal of bacterial plaque on the 7th and 55.83% on the 15th days. Although the electric toothbrush removed more bacterial plaque than the conventional toothbrush, the difference was not statistically significant.

Conclusion:   Both the conventional and the electric toothbrushes were effective in removing bacterial plaque within the elderly group. More studies are necessary to test the efficacy of electric toothbrushes in relation to conventional toothbrushes for elderly patients.
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http://dx.doi.org/10.1111/j.1741-2358.2012.00635.xDOI Listing
September 2020

SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.

Aging Cell 2014 Oct 16;13(5):787-96. Epub 2014 Jun 16.

Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.
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http://dx.doi.org/10.1111/acel.12220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172519PMC
October 2014

Clinical comparison of the effectiveness of single-file reciprocating systems and rotary systems for removal of endotoxins and cultivable bacteria from primarily infected root canals.

J Endod 2014 May 2;40(5):625-9. Epub 2014 Feb 2.

Endodontic Division, Department of Restorative Dentistry, Fluminense Federal University, Niteroi, Rio de Janeiro, Brazil.

Introduction: This clinical study was conducted to compare the effectiveness of single-file reciprocating systems and rotary systems in removing endotoxins and cultivable bacteria from primarily infected root canals.

Methods: Forty-eight primarily infected root canals were selected and randomly divided into 4 groups: WaveOne (Dentsply Maillefer, Ballaigues, Switzerland) (n = 12); Reciproc (VDW, Munich, Germany) (n = 12), ProTaper (Dentsply Maillefer) (n = 12), and Mtwo (VDW) (n = 12). Samples were collected before and after chemomechanical preparation. The irrigation was performed by using 2.5% sodium hypochlorite. A chromogenic limulus amebocyte lysate assay test was used to quantify endotoxins. Culture techniques were used to determine bacterial colony-forming unit counts.

Results: In the baseline samples (ie, samples collected before chemomechanical preparation), endotoxins and cultivable bacteria were recovered from 100% of the root canal samples. No differences were found in the median percentage values of endotoxin reduction achieved with reciprocating systems (ie, WaveOne [95.15%] and Reciproc [96.21%]) and with rotary systems (ie, ProTaper [97.98%] and Mtwo [96.34%]) (P < .05). Both single-file reciprocating systems (ie, WaveOne [99.45%] and Reciproc [99.93%]) and rotary systems (ProTaper [99.85%] and Mtwo [99.41%]) were effective in reducing the cultivable bacteria (all P < .05). Moreover, the culture analysis revealed no differences in bacterial load reduction (P > .05).

Conclusions: Both single-file reciprocating systems (ie, WaveOne and Reciproc instruments) and rotary systems (ie, ProTaper and Mtwo instruments) showed similar effectiveness in reducing endotoxins and cultivable bacteria from primarily infected root canals, but they were not able to eliminate them from all root canals analyzed.
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http://dx.doi.org/10.1016/j.joen.2013.12.006DOI Listing
May 2014

The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

Eur Heart J 2015 Jan 6;36(1):51-9. Epub 2014 Mar 6.

Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

Aims: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture.

Methods And Results: Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis.

Conclusion: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.
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http://dx.doi.org/10.1093/eurheartj/ehu095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286317PMC
January 2015

Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis.

Cancer Cell 2014 Jan;25(1):12-9

Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Paul F. Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Why does cancer risk increase as we age? Frequently attributed to the multi-hit hypothesis and the time required to accumulate genomic mutations, this question is a matter of ongoing debate. Here, we propose that the normal decline in oxidative metabolism during aging constitutes an early and important "hit" that drives tumorigenesis. Central to these metabolic changes are the sirtuins, a family of NAD(+)-dependent deacylases that have evolved as coordinators of physiological responses to nutrient intake and energetic demand. Thus, the modulation of sirtuins might be a fruitful approach to reversing the age-related metabolic changes that could underlie tumorigenesis.
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http://dx.doi.org/10.1016/j.ccr.2013.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970212PMC
January 2014

Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.

Cell 2013 Dec;155(7):1624-38

Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia. Electronic address:

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
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http://dx.doi.org/10.1016/j.cell.2013.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076149PMC
December 2013

Metformin improves healthspan and lifespan in mice.

Nat Commun 2013 ;4:2192

Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA.

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
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http://dx.doi.org/10.1038/ncomms3192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736576PMC
February 2014