Publications by authors named "Maria Cristina Cintra Gomes-Marcondes"

32 Publications

Fish Oil Diet during Pre-mating, Gestation, and Lactation in Adult Offspring Rats on Cancer Cachexia Prevention.

Mol Nutr Food Res 2021 Mar 2:e2000863. Epub 2021 Mar 2.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, Campinas, Brazil.

Scope: Nutritional supplementation of the maternal diet can modify the cancer susceptibility in adult offspring. Therefore, the authors evaluate the effects of a fish-oil diet administered to a long-term, during pre-mating, gestation, and lactation, in reducing cancer-cachexia damages in adult Walker-256 tumor-bearing offspring.

Methods And Results: Female rats receive control or fish oil diet during pre-mating, gestation, and lactation. After weaning, male offspring are fed the control diet until adulthood and distributed in (C) control adult-offspring; (W) adult tumor-bearing offspring; (OC) adult-offspring of maternal fish oil diet; (WOC) adult tumor-bearing offspring of maternal fish oil diet groups. Fat body mass is preserved, muscle expression of mechanistic target of rapamicin (mTOR) and eukariotic binding protein of eukariotic factor 4E (4E-BP1) is modified, being associated with lower 20S proteasome protein expression, and the liver alanine aminotransferase (ALT) enzyme content maintained in the WOC group. Also, the OC group shows reduced triglyceridemia.

Conclusion: In this experimental model of cachexia, the long-term maternal supplementation is a positive strategy to improve liver function and lipid metabolism, as well as to modify muscle proteins expression in the mTOR pathway and also reduce the 20S muscle proteasome protein, without altering the tumor development and muscle wasting in adult tumor-bearing offspring.
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http://dx.doi.org/10.1002/mnfr.202000863DOI Listing
March 2021

Serum and Muscle H NMR-Based Metabolomics Profiles Reveal Metabolic Changes Influenced by a Maternal Leucine-Rich Diet in Tumor-Bearing Adult Offspring Rats.

Nutrients 2020 Jul 16;12(7). Epub 2020 Jul 16.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas (UNICAMP), Rua Monteiro Lobato, 255, Campinas, SP 13083862, Brazil.

A maternal leucine-rich diet showed a positive effect on the gastrocnemius muscle of adult tumor-bearing offspring. To improve the understanding of the metabolic alterations of cancer cachexia and correlate this to preventive treatment, we evaluated the H NMR metabolic profiles from serum and gastrocnemius muscle samples of adult Wistar rats. These profiles were initially analyzed, and chemometrics tools were applied to investigate the following groups: C, control group; W, tumor-bearing group; L, the group without tumors and with a maternal leucine-rich diet; WL, the tumor-bearing group with a maternal leucine-rich diet. Tumor growth that led to a high protein breakdown in the W group was correlated to serum metabolites such as tyrosine, phenylalanine, histidine, glutamine, and tryptophan amino acids and uracil. Also, decreased muscle lactate, inversely to serum content, was found in the W group. Conversely, in the WL group, increased lactate in muscle and serum profiles was found, which could be correlated to the maternal diet effect. The muscle lipidomics and NAD, NADP, lysine, 4-aminohippurate, and glutamine metabolites pointed to modified energy metabolism and lower muscle mass loss in the WL group. In conclusion, this exploratory metabolomics analyses provided novel insights related to the Walker-256 tumor-bearing offspring metabolism modified by a maternal leucine-rich diet and the next steps in its investigation.
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http://dx.doi.org/10.3390/nu12072106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400806PMC
July 2020

Aerobic training prevents cardiometabolic changes triggered by myocardial infarction in ovariectomized rats.

J Cell Physiol 2021 Feb 7;236(2):1105-1115. Epub 2020 Jul 7.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.

This study aimed to evaluate the impact of aerobic training (AT) on autonomic, cardiometabolic, ubiquitin-proteasome activity, and inflammatory changes evoked by myocardial infarction (MI) in ovariectomized rats. Female Wistar rats were ovariectomized and divided into four groups: sedentary + sham (SS), sedentary + MI (SI), AT + sham surgery (TS), AT + MI (TI). AT was performed on a treadmill for 8 weeks before MI. Infarcted rats previously subjected to AT presented improved physical capacity, increased interleukin-10, and decreased pro-inflammatory cytokines. Metabolomic analysis identified and quantified 62 metabolites, 9 were considered significant by the Vip Score. SS, SI, and TS groups presented distinct metabolic profiles; however, TI could not be distinguished from the SS group. MI dramatically increased levels of dimethylamine, and AT prevented this response. Our findings suggest that AT may be useful in preventing the negative changes in functional, inflammatory, and metabolic parameters related to MI in ovariectomized rats.
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http://dx.doi.org/10.1002/jcp.29919DOI Listing
February 2021

and Honey Solution and Their Ethanolic Extraction Solution Could Act on Metastasis-Regulating Processes in Walker 256 Tumor Tissues In Vivo?

Nutr Cancer 2020 Jul 1:1-9. Epub 2020 Jul 1.

Department of Structural and Functional Biology, Laboratory of Nutrition and Cancer, Institute of Biology, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Research has shown that both and honey have anticancer and nutrition properties, including the inhibition of metastasis. In order to evaluate the effect of a solution of and honey (A) and their ethanolic fraction (F) on metastasis-regulating processes in primary tumors, Wistar rats were subcutaneously implanted with Walker 256 tumors and treated with A and F (670 µl/kg by gavage, daily for 21 days). An analysis of the primary tumor tissues of these animals showed a decrease in N-cadherin expression in groups WA and WF, with a concomitant increase in E-cadherin expression in group WA compared to the control group. Cathepsin D activity was also decreased in the tumor tissues from groups WA and WF. In addition, the number of blood vessels and their diameter significantly reduced in tumor tissues from groups WA and WF compared to those from control group. UHPLC-ESI-MS/MS analysis of the samples A and F, suggested presence of molecules with verified antitumor activity, including caffeic acid, ferulic acid, mannose, aloin A, aloin B, pinocembrin, chrysin, and kaempferol. These data showed that treatment with A and F could reduce the metastatic propensity of tumors by modulating neoangiogenesis and the process of epithelial-to-mesenchymal transition.
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http://dx.doi.org/10.1080/01635581.2020.1784443DOI Listing
July 2020

H-NMR Based Serum Metabolomics Identifies Different Profile between Sarcopenia and Cancer Cachexia in Ageing Walker 256 Tumour-Bearing Rats.

Metabolites 2020 Apr 21;10(4). Epub 2020 Apr 21.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas (UNICAMP), Campinas 13083862, Brazil.

Sarcopenia among the older population has been growing over the last few years. In addition, the incidence of cancers increases with age and, consequently, the development of cachexia related cancer. Therefore, the elucidation of the metabolic derangements of sarcopenia and cachexia are important to improve the survival and life quality of cancer patients. We performed the H-NMR based serum metabolomics in adult (A) and ageing (S) Walker 256 tumour-bearing rats in different stages of tumour evolution, namely intermediated (Wi) and advanced (Wa). Among 52 serum metabolites that were identified, 21 were significantly increased in S and 14 and 19 decreased in the Wi and Wa groups, respectively. The most impacted pathways by this metabolic alteration were related by amino acid biosynthesis and metabolism, with an upregulation in S group and downregulation in Wi and Wa groups. Taken together, our results suggest that the increase in metabolic profile in ageing rats is associated with the higher muscle protein degradation that releases several metabolites, especially amino acids into the serum. On the other hand, we hypothesise that the majority of metabolites released by muscle catabolism are used by tumours to sustain rapid cell proliferation and tumorigenesis.
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http://dx.doi.org/10.3390/metabo10040161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240940PMC
April 2020

Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats.

Sci Rep 2019 10 29;9(1):15529. Epub 2019 Oct 29.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, Campinas, SP, Brazil.

Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein + 3% leucine]). After 20 days of tumour evolution, the animals underwent -fludeoxyglucose positron emission computed tomography (F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
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http://dx.doi.org/10.1038/s41598-019-52112-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820796PMC
October 2019

Maternal Leucine-Rich Diet Minimises Muscle Mass Loss in Tumour-bearing Adult Rat Offspring by Improving the Balance of Muscle Protein Synthesis and Degradation.

Biomolecules 2019 06 13;9(6). Epub 2019 Jun 13.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, UNICAMP, Rua Monteiro Lobato, 255, Campinas, São Paulo 13083862, Brazil.

Cachexia syndrome can affect cancer patients and new prevention strategies are required. Maternal nutritional supplementation can modify metabolic programming in the offspring, which lasts until adulthood. This could be a good approach against diseases such as cancer. A 3% leucine-rich diet treatment improved muscle protein turnover by modifying the mTOR and proteolytic pathways, thus we analysed whether maternal supplementation could ameliorate muscle protein turnover in adult offspring tumour-bearing rats. Pregnant Wistar rats received a control diet or 3% leucine-rich diet during pregnancy/lactation, and their weaned male offspring received a control diet until adulthood when they were distributed into following groups (n = 7-8 per group): C, Control; W, tumour-bearing; L, without tumour with a maternal leucine-rich diet; and WL, tumour-bearing with a maternal leucine-rich diet. Protein synthesis and degradation were assessed in the gastrocnemius muscle, focusing on the mTOR pathway, which was extensively altered in W group. However, the WL adult offspring showed no decrease in muscle weight, higher food intake, ameliorated muscle turnover, activated mTOR and p70S6K, and maintained muscle cathepsin H and calpain activities. Maternal leucine nutritional supplementation could be a positive strategy to improve muscle protein balance in cancer cachexia-induced muscle damage in adult offspring rats.
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http://dx.doi.org/10.3390/biom9060229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628133PMC
June 2019

A leucine-rich diet modulates the mTOR cell signalling pathway in the gastrocnemius muscle under different Walker-256 tumour growth conditions.

BMC Cancer 2019 Apr 11;19(1):349. Epub 2019 Apr 11.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas, UNICAMP, CP 6109, 13083862, Campinas, São Paulo, Brazil.

Background: The exact signalling mechanism of the mTOR complex remains a subject of constant debate, even with some evidence that amino acids participate in the same pathway as used for insulin signalling during protein synthesis. Therefore, this work conducted further study of the actions of amino acids, especially leucine, in vivo, in an experimental model of cachexia. We analysed the effects of a leucine-rich diet on the signalling pathway of protein synthesis in muscle during a tumour growth time-course.

Methods: Wistar rats were distributed into groups based on Walker-256 tumour implant and subjected to a leucine-rich diet and euthanised at three different time points following tumour development (the 7th, 14th and 21st day). We assessed the mTOR pathway key-proteins in gastrocnemius muscle, such as RAG-A-GTPase, ERK/MAP4K3, PKB/Akt, mTOR, p70S6K1, Jnk, IRS-1, STAT3, and STAT6 comparing among the experimental groups. Serum WF (proteolysis-induced factor like from Walker-256 tumour) and muscle protein synthesis and degradation were assessed.

Results: The tumour-bearing group had increased serum WF content, and the skeletal-muscle showed a reduction in IRS-1 and RAG activation, increased PKB/Akt and Erk/MAP4K3 on the 21st day, and maintenance of p70S6K1, associated with increases in muscle STAT-3 and STAT-6 levels in these tumour-bearing rats.

Conclusion: Meanwhile, the leucine-rich diet modulated key steps of the mTOR pathway by triggering the increased activation of RAG and mTOR and maintaining JNK, STAT-3 and STAT-6 levels in muscle, leading to an increased muscle protein synthesis, reducing the degradation during tumour evolution in a host, minimising the cancer-induced damages in the cachectic state.
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http://dx.doi.org/10.1186/s12885-019-5448-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458732PMC
April 2019

Leucine can modulate the expression of proteins related to protein degradation signalling under mTOR inhibition in C2C12 cells.

Cell Mol Biol (Noisy-le-grand) 2018 Jul 30;64(10):73-78. Epub 2018 Jul 30.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, Zip Code 13083862, Campinas, Sao Paulo, Brazil.

Many metabolic syndromes lead to energetic disturbs which ends to an intense catabolic state. The branched-chain amino acid leucine shows very positive effects on muscle protein metabolism. However, it is still not clear how leucine acts improving the protein turnover. This study aimed to evaluate in vitro the effects of leucine supplementation in minimising the signalling pathway of protein degradation when mTOR was inhibited. Our studies were conducted in murine C2C12 myotubes exposed to 2mM leucine or 2mM isoleucine in control situation and compared to the inhibition of mTOR by rapamycin. Then, the expression of proteins related to protein synthesis and degradation signalling pathway was obtained by Western Blot. At this concentration, the leucine was sufficient to maintain the expression of proteins evaluated as in control situation. However, when the cells were exposed to rapamycin (80nM), leucine inhibited the expression of SMAD and FoxO3a, showing that leucine was able to modulate the degradation pathway when protein synthesis is compromised. Furthermore, leucine had no effect in modifying the expression of subunits of ubiquitin-proteasome system, showing that leucine had no direct effect in ubiquitin-proteasome system, but acted leading to the phosphorylation of SMAD and FoxO3, which inhibited the activity of transcriptional of these proteins. No similar results were observed in cells exposed to isoleucine under the same experimental protocol, likely showing that leucine has specific action over another branched-chain amino acids. In conclusion, the present study shows that leucine can modulate degradation pathways even under inhibition of mTOR by rapamycin.
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July 2018

Maternal nutritional supplementation with fish oil and/or leucine improves hepatic function and antioxidant defenses, and minimizes cachexia indexes in Walker-256 tumor-bearing rats offspring.

Nutr Res 2018 03 28;51:29-39. Epub 2017 Dec 28.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, UNICAMP, Rua Monteiro Lobato, 255, Campinas, São Paulo, 13083862, Brazil. Electronic address:

In this study, we hypothesized that throughout the pregnancy/weaning period, nutritional supplementation with leucine (which improves protein synthesis) and/or fish oil (rich in omega-3, which modulates oxidative stress) can minimize/improve cachexia-induced damage in rat offspring. Thus, we investigated the maternal supplementation with these nutrients over the modulation of cachexia index and liver function in tumor-bearing rats offspring. Pregnant rats were fed control, leucine, omega-3, and leucine/omega-3 diets, which were given throughout the gestational and weaning periods. The male offspring were subjected to a control diet until adulthood (120 days) and then distributed into 5 groups (n=4-6 per group): C, Control; W, tumor-bearing; WL, tumor-bearing group with a maternal leucine-rich diet; WO, tumor-bearing group with a maternal omega-3 diet; and WLO, tumor-bearing group with a maternal leucine-rich and omega-3 diet. The W group had a higher cachexia index (31.83 ± 2.9%), but this parameter decreased in the WO (P=0.0380) and WLO groups (P=0.0187). In addition, the W group had a lower survival rate, and the WLO group exhibited a trend toward increased survival (P=0.0505). The hepatic function in maternal supplemented groups was preserved, while the W group exhibited an increased aspartate-aminotransferase/alanine-aminotransferase ratios (P=0.0152) and also enhanced liver oxidative stress, with higher alkaline phosphatase (P=0.0190) and superoxide dismutase (P=0.0190) activities, and trended toward to higher malondialdehyde content (P=0.0556). In contrast, the maternal-supplemented groups had similar liver enzymes and malondialdehyde contents. Thus, we concluded that supplementing the maternal diet modulated/improved liver antioxidant responses and ameliorated the cachexia state in tumor-bearing rat offspring.
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http://dx.doi.org/10.1016/j.nutres.2017.12.003DOI Listing
March 2018

L-leucine dietary supplementation modulates muscle protein degradation and increases pro-inflammatory cytokines in tumour-bearing rats.

Cytokine 2017 08 8;96:253-260. Epub 2017 May 8.

Department of Structural and Functional Biology, Biology Institute, State University of Campinas, UNICAMP, CP 6109, 13083862 Campinas, Sao Paulo, Brazil. Electronic address:

Cancer cachexia is characterised by involuntary weight loss associated with systemic inflammation and metabolic changes. Studies aimed at maintaining lean body mass in cachectic tumour-bearing hosts have made important contributions reducing the number of deaths and improving the quality of life. In recent years, leucine has demonstrated effective action in maintaining lean body mass by decreasing muscle protein degradation. Currently, there is a growing need to understand how leucine stimulates protein synthesis and acts protectively in a cachectic organism. Thus, this study aimed to assess the effects of a leucine-rich diet on protein degradation signalling in muscle over the course of tumour growth. Animals were distributed into four experimental groups, which did or did not receive 2×10 viable Walker-tumour cells. Some were fed a leucine-rich diet, and the groups were subsequently sacrificed at three different time points of tumour evolution (7th, 14th, and 21st days). Protein degradation signals, as indicated by ubiquitin-proteasome subunits (11S, 19S, and 20S) and pro- and anti-inflammatory cytokines, were analysed in all experimental groups. In tumour-bearing animals without nutritional supplementation (W7, W14, and W21 groups), we observed that the tumour growth promoted a concurrent decrease in muscle protein, a sharp increase in pro-inflammatory cytokines (TNFα, IL-6, and IFNγ), and a progressive increase in proteasome subunits (19S and 20S). Thus, the leucine-supplemented tumour-bearing groups showed improvements in muscle mass and protein content, and in this specific situation, the leucine-rich diet led to an increase on the day in cytokine profile and proteasome subunits mainly on the 14th day, which subsequently had a modulating effect on tumour growth on the 21st day. These results indicate that the presence of leucine in the diet may modulate important aspects of the proteasomal pathway in cancer cachexia and may prevent muscle wasting due to the decrease in the cachexia index.
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http://dx.doi.org/10.1016/j.cyto.2017.04.019DOI Listing
August 2017

Long-term Leucine Supplementation Improves Metabolic But Not Molecular Responses in the Skeletal Muscle of Trained Rats Submitted to Exhaustive Exercise.

J Am Coll Nutr 2017 02 12;36(2):81-87. Epub 2016 Dec 12.

a Department of Structural and Functional Biology , Institute of Biology, University of Campinas (UNICAMP) , Campinas , São Paulo , BRAZIL.

Aim: Although there is some evidence of an ergogenic effect of leucine supplementation on acute response to exercise, there is a paucity of information on whether long-term leucine supplementation influences the adaptive response to chronic endurance training and performance. The main aim of our study was to assess the role of long-term leucine supplementation on molecular and metabolic response in skeletal muscle of trained rats after an exhaustion test.

Methods: Twenty-four male Wistar rats were randomly allocated into 4 groups. Two of them (control and trained groups) received a balanced control diet (18% protein) and the other 2 (control leucine and trained leucine groups) received a leucine-rich diet (15% protein with 3% leucine) for 6 weeks. The trained groups were submitted to 1 hour of swimming exercise, 5 d/wk for 6 weeks. Three days after the exercise training period, trained groups were submitted to swimming exercise until exhaustion and muscle metabolic and molecular parameters were assessed.

Results: Endurance training increased citrate synthase activity significantly, whereas exercise until exhaustion increased cytokine levels and led to a lack of activation of phosphorylation of the signaling intermediates assessed. Long-term leucine supplementation enhanced muscle glycogen level in trained rats and citrate synthase activity in sedentary ones. However, it failed to enhance endurance performance of trained rats submitted to an exhaustion test and did not prevent exercise-induced reduction in Akt and mTOR activation.

Conclusion: Long-term leucine supplementation can enhance citrate synthase activity by itself in sedentary individuals and glycogen content when combined with exercise; however, it does not improve endurance performance or prevent Akt and mTOR exercise-induced inhibition.
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http://dx.doi.org/10.1080/07315724.2016.1183532DOI Listing
February 2017

Leucine-rich diet alters the H-NMR based metabolomic profile without changing the Walker-256 tumour mass in rats.

BMC Cancer 2016 10 3;16(1):764. Epub 2016 Oct 3.

Department of Structural and Functional Biology, Laboratory of Nutrition and Cancer, Institute of Biology, University of Campinas-UNICAMP, Campinas, 13083862, São Paulo, Brazil.

Background: Cachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, particularly leucine, has been used to minimise loss of muscle tissue, although few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumour-bearing host. Therefore, the present study evaluated whether a leucine-rich diet affects metabolomic derangements in serum and tumour tissues in tumour-bearing Walker-256 rats (providing an experimental model of cachexia).

Methods: After 21 days feeding Wistar female rats a leucine-rich diet, distributed in L-leucine and LW-leucine Walker-256 tumour-bearing groups, we examined the metabolomic profile of serum and tumour tissue samples and compared them with samples from tumour-bearing rats fed a normal protein diet (C - control; W - tumour-bearing groups). We utilised H-NMR as a means to study the serum and tumour metabolomic profile, tumour proliferation and tumour protein synthesis pathway.

Results: Among the 58 serum metabolites examined, we found that 12 were altered in the tumour-bearing group, reflecting an increase in activity of some metabolic pathways related to energy production, which diverted many nutrients toward tumour growth. Despite displaying increased tumour cell activity (i.e., higher Ki-67 and mTOR expression), there were no differences in tumour mass associated with changes in 23 metabolites (resulting from valine, leucine and isoleucine synthesis and degradation, and from the synthesis and degradation of ketone bodies) in the leucine-tumour group. This result suggests that the majority of nutrients were used for host maintenance.

Conclusion: A leucine rich-diet, largely used to prevent skeletal muscle loss, did not affect Walker 256 tumour growth and led to metabolomic alterations that may partially explain the positive effects of leucine for the whole tumour-bearing host.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048609PMC
http://dx.doi.org/10.1186/s12885-016-2811-2DOI Listing
October 2016

Antimelanoma effect of Salmonella Typhimurium integration host factor mutant in murine model.

Future Oncol 2016 Oct 22;12(20):2367-78. Epub 2016 Jun 22.

Department of Genetics, Evolution & Bioagents, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.

Aim: This study aimed to evaluate an attenuated Salmonella ihfA-null mutant strain as therapeutic agent to control tumor growth.

Materials & Methods: After bacterial toxicity evaluation, C57BL/6JUnib mice were inoculated with B16F10 cells and treated with two Salmonella strains (LGBM 1.1 and LGBM 1.41).

Results: LGBM 1.1 can reduce tumor mass, but it exerts some toxic effects. Although LGBM 1.41 is less toxic than LGBM 1.1, it does not reduce tumor mass significantly. Indeed, animals treated with LGBM 1.41 present only slightly initial delay in tumor progression and increased survival rate as compared with the control.

Conclusion: The null-mutants of ihfA gene of Salmonella Typhimurium could be a promising candidate for melanoma treatment.
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http://dx.doi.org/10.2217/fon-2015-0062DOI Listing
October 2016

Long-term leucine supplementation aggravates prolonged strenuous exercise-induced cardiovascular changes in trained rats.

Exp Physiol 2016 07 14;101(7):811-20. Epub 2016 Jun 14.

Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), 13083-862 Campinas, São Paulo, Brazil.

New Findings: What is the central question of this study? Can long-term leucine supplementation prevent prolonged strenuous endurance exercise induced cardiac injury? What is the main finding and its importance? Prolonged endurance exercise does not seem to exceed cardiac energetic capacity, hence it does not represent an energy threat to this organ, at least in trained subjects. However, it may induce, in susceptible individuals, a state of cardiac electrical instability, which has been associated with ventricular arrhythmias and sudden cardiac death. This situation might be worsened when combined with leucine supplementation, which leads to increased blood pressure and cardiac injury. Leucine supplementation failed to prevent cardiac fatigue symptoms and may aggravate prolonged strenuous exercise-induced cardiovascular disturbances in trained rats. Observational studies have raised concerns that prolonged strenuous exercise training may be associated with increased risk of cardiac arrhythmia and even primary cardiac arrest or sudden death. It has been demonstrated that leucine can reduce prolonged exercise-induced muscle damage and accelerate the recovery process. The aim of this study was to investigate the effects of prolonged strenuous endurance exercise on cardiovascular parameters and biomarkers of cardiac injury in trained adult male rats and assess the use of leucine as an auxiliary substance to prevent the likely cardiac adverse effects caused by strenuous exercise. Twenty-four male Wistar rats were randomly allocated to receive a balanced control diet (18% protein) or a leucine-rich diet (15% protein plus 3% leucine) for 6 weeks. The rats were submitted to 1 h of exercise, 5 days per week for 6 weeks. Three days after the training period, the rats were submitted to swimming exercise until exhaustion, and cardiac parameters were assessed. Exercising until exhaustion significantly increased cardiac biomarker levels, cytokines and glycogen content inhibited protein synthesis signalling and led to cardiac electrical disturbances. When combined with exercise, leucine supplementation led to greater increases in the aforementioned parameters and also a significant increase in blood pressure and protein degradation signalling. We report, for the first time, that leucine supplementation not only fails to prevent cardiac fatigue symptoms, but may also aggravate prolonged strenuous exercise-induced cardiovascular disturbances in trained rats. Furthermore, we find that exercising until exhaustion can cause cardiac electrical disturbances and damage cardiac myocytes.
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http://dx.doi.org/10.1113/EP085704DOI Listing
July 2016

Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals.

J Cachexia Sarcopenia Muscle 2016 12 24;7(5):577-586. Epub 2016 Feb 24.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Institute of Biology State University of Campinas, Campinas 13083-970 São Paulo Brazil.

Background: The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart.

Methods: Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity.

Results: Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity.

Conclusions: Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.
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http://dx.doi.org/10.1002/jcsm.12100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793899PMC
December 2016

Dietary leucine supplementation minimises tumour-induced damage in placental tissues of pregnant, tumour-bearing rats.

BMC Cancer 2016 Feb 4;16:58. Epub 2016 Feb 4.

Department of Structural and Functional Biology, Biology Institute, State University of Campinas, UNICAMP, CP 6109, Campinas, São Paulo, 13083862, Brazil.

Background: The occurrence of cancer during pregnancy merges two complex, poorly understood metabolic and hormonal conditions. This association can exacerbate the conditions of both the mother and the foetus. The branched-chain amino acid leucine enhances cellular activity, particularly by increasing protein synthesis. This study aimed to analyse the modulatory effect of a leucine-rich diet on direct and indirect tumour-induced placental damage. This was accomplished by evaluating the expression of genes involved in protein synthesis and degradation and assessing anti-oxidant enzyme activity in placental tissues collected from pregnant, tumour-bearing rats.

Results: Pregnant rats were either implanted with Walker 256 tumour cells or injected with ascitic fluid (to study the indirect effects of tumour growth) and then fed a leucine-rich diet. Animals in a control group underwent the same procedures but were fed a normal diet. On the 20(th) day of pregnancy, tumour growth was observed. Dams fed a normoprotein diet showed the greatest tumour growth. Injection with ascitic fluid mimicked the effects of tumour growth. Decreased placental protein synthesis and increased protein degradation were observed in both the tumour-bearing and the ascitic fluid-injected groups that were fed a normoprotein diet. These effects resulted in low placental DNA and protein content and high lipid peroxidation (measured by malondialdehyde content). Decreased placental protein synthesis-related gene expression was observed in the tumour group concomitant with increased expression of genes encoding protein degradation-associated proteins and proteolytic subunits.

Conclusions: Consumption of a leucine-rich diet counteracted the effects produced by tumour growth and injection with ascitic fluid. The diet enhanced cell signalling, ameliorated deficiencies in DNA and protein content, and balanced protein synthesis and degradation processes in the placenta. The improvements in cell signalling included changes in the mTOR/eIF pathway. In conclusion, consumption of a leucine-rich diet improved placental metabolism and cell signalling in tumour-bearing rats, and these changes reduced the deleterious effects caused by tumour growth.
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http://dx.doi.org/10.1186/s12885-016-2103-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743202PMC
February 2016

Oral Administration of Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) and Honey Improves the Host Body Composition and Modulates Proteolysis Through Reduction of Tumor Progression and Oxidative Stress in Rats.

J Med Food 2015 Oct 9;18(10):1128-35. Epub 2015 Apr 9.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Institute of Biology, State University of Campinas-UNICAMP , Campinas, São Paulo, Brazil .

Oxidative stress has a dual role in cancer; it is linked with tumorigenic events and host wasting, as well as senescence and apoptosis. Researchers have demonstrated the importance of coadjuvant therapies in cancer treatment, and Aloe vera and honey have immunomodulatory, anticancer, and antioxidant properties. The preventive and therapeutic effects of Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) and honey in tumor progression and host wasting were analyzed in Walker 256 carcinoma-bearing rats. The animals were distributed into the following groups: C=control-untreated, W=tumor-untreated, WA=treated after tumor induction, A=control-treated, AW=treated before tumor induction, and AWA=treated before and after tumor induction. Proteolysis and oxidative stress were analyzed in the tumor, liver, muscle, and myocardial tissues. The results suggest that the Aloe vera and honey treatment affect the tumor and host by different mechanisms; the treatment-modulated host wasting and cachexia, whereas it promoted oxidative stress and damage in tumor tissues, particularly in a therapeutic context (WA).
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http://dx.doi.org/10.1089/jmf.2014.0129DOI Listing
October 2015

A leucine-rich diet modulates the tumor-induced down-regulation of the MAPK/ERK and PI3K/Akt/mTOR signaling pathways and maintains the expression of the ubiquitin-proteasome pathway in the placental tissue of NMRI mice.

Biol Reprod 2015 Feb 13;92(2):49. Epub 2014 Nov 13.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil

Placental tissue injury is concomitant with tumor development. We investigated tumor-driven placental damage by tracing certain steps of the protein synthesis and degradation pathways under leucine-rich diet supplementation in MAC16 tumor-bearing mice. Cell signaling and ubiquitin-proteasome pathways were assessed in the placental tissues of pregnant mice, which were distributed into three groups on a control diet (pregnant control, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid) and three other groups on a leucine-rich diet (pregnant, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid). MAC tumor growth down-regulated the cell-signaling pathways of the placental tissue and decreased the levels of IRS-1, Akt/PKB, Erk/MAPK, mTOR, p70S6K, STAT3, and STAT6 phosphorylated proteins, as assessed by the multiplex Millipore Luminex assay. Leucine supplementation maintained the levels of these proteins within the established cell-signaling pathways. In the tumor-bearing group (MAC) only, the placental tissue showed increased PC5 mRNA expression, as assessed by quantitative RT-PCR, decreased 19S and 20S protein expression, as assessed by Western blot analysis, and decreased placental tyrosine levels, likely reflecting up-regulation of the ubiquitin-proteasome pathway. Similar effects were found in the pregnant injected with MAC-ascitic fluid group, confirming that the effects of the tumor were mimicked by MAC-ascitic fluid injection. Although tumor progression occurred, the degradation pathway-related protein levels were modulated under leucine-supplementation conditions. In conclusion, tumor evolution reduced the protein expression of the cell-signaling pathway associated with elevated protein degradation, thereby jeopardizing placental activity. Under the leucine-rich diet, the impact of cancer on placental function could be minimized by improving the cell-signaling activity and reducing the proteolytic process.
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http://dx.doi.org/10.1095/biolreprod.114.123307DOI Listing
February 2015

Glycine improves biochemical and biomechanical properties following inflammation of the achilles tendon.

Anat Rec (Hoboken) 2015 Mar 2;298(3):538-45. Epub 2014 Sep 2.

Department of Structural and Functional Biology, Institute of Biology, State University of Campinas 13083-863 CP 6109, Campinas, SP, Brazil.

Tendinopathy of the Achilles tendon is a clinical problem that motivates the scientific community to search for treatments that assist in restoring its functional properties. Glycine has broad biological effects, acting as a modulator of the inflammatory cascade, and is the predominant amino acid in collagen. A 5% glycine diet provided beneficial effects against toxicity and inflammation since glycine may restructure the collagen molecules faster due to its broad anti-inflammatory effects. The purpose was analyze the effects of a 5% glycine diet in rats as a treatment for the inflammatory process. The experimental groups were as follows: C (control group), G1 and G3 (inflammatory group), and G2 and G4 (glycine+inflammatory group). G1 and G2 were euthanized 8 days following injury, and G3 and G4 were euthanized 22 days following injury. The concentrations of hydroxyproline, non-collagenous proteins, and glycosaminoglycans, as well as the activity of MMP-2 and -9 were analyzed. Biomechanical and morphological tests were employed. Higher concentrations of hydroxyproline and glycosaminoglycans were found in G4 and an increased activity of MMP-2 was found in G2. Higher birefringence was noted in group G2. The biomechanical results indicated that the tendon was more resistant to loading to rupture upon treatment with a glycine diet in group G4. Glycine induced the synthesis of important components of the tendon. A rapid remodeling was noted when compared with the inflamed-only groups. These data suggest that glycine may be a beneficial supplement for individuals with inflammation of the Achilles tendon.
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http://dx.doi.org/10.1002/ar.23041DOI Listing
March 2015

Hepatoprotective effect of Arctium lappa root extract on cadmium toxicity in adult Wistar rats.

Biol Trace Elem Res 2014 Aug 15;160(2):250-7. Epub 2014 Jun 15.

Departamento de Ciências Biológicas, Universidade Estadual do Paraná/Campus Paranaguá, Rua Comendador Correia Junior, 117-Centro, Paranaguá, Paraná, 83203-560, Brazil,

This study was performed to determine the effects of Arctium lappa (Al) to protect against cadmium damage in the rat liver. Male rats received a single i.p. dose of CdCl2 (1.2 mg/kg body weight (BW)) with or without Al extract administered daily by gavage (300 mg/kg BW) for 7 or 56 days. After 7 days, Al caused plasma transaminase activity to diminish in groups Al (glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT)) and CdAl (GPT). After 56 days, GOT and GPT plasma activities were reduced in the Cd group. No alteration in plasma levels of creatinine, total bilirubin, and total protein were observed. GOT liver activity increased in the Cd group. No alteration was observed in superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and malondialdehyde (MDA) dosage. In the Cd group, hepatocyte proportion decreased and sinusoid capillary proportion increased. In the Al and CdAl groups, the nuclear proportion increased and the cytoplasmic proportion decreased. The hepatocyte nucleus density reduced in Cd and increased in the Al group. After 56 days, there was no alteration in the Cd group. In Al and CdAl groups, the nuclear proportion increased without cytoplasmic proportion variation, but the sinusoid capillary proportion was reduced. The hepatocyte nucleus density decreased in the Cd group and increased in the Al and CdAl groups. In conclusion, the liver function indicators showed that A. lappa protected the liver against cadmium toxicity damage.
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http://dx.doi.org/10.1007/s12011-014-0040-6DOI Listing
August 2014

Melatonin reduces oxidative stress and cardiovascular changes induced by stanozolol in rats exposed to swimming exercise.

Eurasian J Med 2013 Oct;45(3):155-62

Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Objective: Anabolic-androgenic steroids (AAS) are nominated for clinical use to promote protein synthesis in many therapeutic conditions. However, the indiscriminate use of AAS is related to hazardous cardiac disturbances and oxidative stress. We designed a study to investigate whether prolonged treatment with high doses of stanozolol modifies the activities of some antioxidant enzymes in the heart in sedentary and trained rats and whether this treatment causes alterations of cardiovascular parameters. In addition, the effectiveness of melatonin as an antioxidant and as a modulator of the cardiovascular side effects of stanozolol (STA) treatment was analyzed.

Materials And Methods: Thirty male Wistar rats were divided into the following six groups: sedentary (S), stanozolol sedentary (SS), stanozolol-melatonin sedentary (SMS), trained (T), stanozolol trained (ST) and stanozolol-melatonin trained (SMT). The stanozolol-treatment rats received 5 mg.kg(-1) by subcutaneous injection before each exercise session (5 d.wk(-1), i.e., 25 mg.kg(-1).wk(-1)), while control groups received only saline solution injection. The melatonin-treatment groups received intraperitoneal injections of melatonin (10 mg.kg(-1)), 5 d.wk(-1) for 6 wk. Electrocardiography, blood pressure and antioxidant enzyme activity measurements were performed at the end of the experimental period for cardiac function and molecular assessment.

Results: This is the first time that the in vivo effects of melatonin treatment on stanozolol-induced cardiovascular side effects have been studied. Stanozolol induced bradycardia and significantly increased cardiac superoxide dismutase and catalase activities. Trained stanozolol-treated rats experienced an increase in blood pressure and relative heart weight, and they developed left cardiac axis deviation. Although melatonin did not prevent cardiac hypertrophy in exercised stanozolol-treated animals, it maintained blood pressure and cardiac catalase activity, and it prevented stanozolol-induced cardiac electrical axis deviation.

Conclusion: In conclusion, under our experimental conditions, chronic stanozolol administration induced mild cardiovascular side effects that were partly attenuated by melatonin treatment. However, these results showed that the combination of melatonin and exercise could minimize the stanozolol side effects in the cardiovascular system.
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http://dx.doi.org/10.5152/eajm.2013.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261421PMC
October 2013

Leucine modulates the effect of Walker factor, a proteolysis-inducing factor-like protein from Walker tumours, on gene expression and cellular activity in C2C12 myotubes.

Cytokine 2013 Oct 5;64(1):343-50. Epub 2013 Jun 5.

Department of Structural and Functional Biology, Biology Institute, State University of Campinas (UNICAMP), CP 6109, 13083-970 Campinas, São Paulo, Brazil.

Cancer-cachexia causes severe weight loss, particularly from the wasting of skeletal muscle, which occurs due to increased protein catabolism and/or decreased protein synthesis. The muscle protein degradation observed in cancer patients is mediated by a specific cytokine, proteolysis-inducing factor (PIF), which is produced by the tumour. This protein increases the ubiquitin-proteasome pathway activity, and the synthesis of muscle protein in these patients can be affected by several factors, including nutrient-related signalling. Some nutrients, such as leucine, can decrease the ubiquitin-proteasome pathway activity and increase the skeletal muscle protein content in cachectic animals. In this study, we investigated the effects of leucine on cell viability, morphology, functional proteasome activity, enzymatic activity, and protein synthesis and degradation in C2C12 myotubes exposed to the proteolysis-inducing factor (PIF)-like protein purified from Walker tumour-bearing rats. Walker factor (WF) had no cytotoxic effects on myotube cells and morphological characteristics were not altered in the presence of WF and/or leucine. However, increased alkaline phosphatase activity was observed. At higher WF concentrations, chymotrypsin-like activity, cathepsin B activity and 20S proteasome gene expression increased. Treating myotubes with leucine before exposure to WF causes leads to a decrease in proteasome activity as well as the activity of chymotrypsin and cathepsin enzymes. Total protein synthesis decreased in WF-treated cells concomitantly as protein degradation increased. After leucine exposure, the observed effects of WF were minimal or even reverted in some cases. Taken together, these results suggest an important modulatory effect for leucine on the effects of WF in C2C12 myotube cells.
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http://dx.doi.org/10.1016/j.cyto.2013.05.018DOI Listing
October 2013

Light aerobic physical exercise in combination with leucine and/or glutamine-rich diet can improve the body composition and muscle protein metabolism in young tumor-bearing rats.

J Physiol Biochem 2012 Dec 30;68(4):493-501. Epub 2012 Mar 30.

Department of Structural and Functional Biology, Biology Institute, State University of Campinas, UNICAMP, 13083-970, Campinas, São Paulo, Brazil.

Nutritional supplementation with some amino acids may influence host's responses and also certain mechanism involved in tumor progression. It is known that exercise influences body weight and muscle composition. Previous findings from our group have shown that leucine has beneficial effects on protein composition in cachectic rat model as the Walker 256 tumor. The main purpose of this study was to analyze the effects of light exercise and leucine and/or glutamine-rich diet in body composition and skeletal muscle protein synthesis and degradation in young tumor-bearing rats. Walker tumor-bearing rats were subjected to light aerobic exercise (swimming 30 min/day) and fed a leucine-rich (3%) and/or glutamine-rich (4%) diet for 10 days and compared to healthy young rats. The carcasses were analyzed as total water and fat body content and lean body mass. The gastrocnemious muscles were isolated and used for determination of total protein synthesis and degradation. The chemical body composition changed with tumor growth, increasing body water and reducing body fat content and total body nitrogen. After tumor growth, the muscle protein metabolism was impaired, showing that the muscle protein synthesis was also reduced and the protein degradation process was increased in the gastrocnemius muscle of exercised rats. Although short-term exercise (10 days) alone did not produce beneficial effects that would reduce tumor damage, host protein metabolism was improved when exercise was combined with a leucine-rich diet. Only total carcass nitrogen and protein were recovered by a glutamine-rich diet. Exercise, in combination with an amino acid-rich diet, in particular, leucine, had effects beyond reducing tumoral weight such as improving protein turnover and carcass nitrogen content in the tumor-bearing host.
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http://dx.doi.org/10.1007/s13105-012-0164-0DOI Listing
December 2012

A leucine-rich diet and exercise affect the biomechanical characteristics of the digital flexor tendon in rats after nutritional recovery.

Amino Acids 2012 Jan 24;42(1):329-36. Epub 2010 Nov 24.

Department of Anatomy, Cell Biology and Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), Campinas, São Paulo, 13083-970, Brazil.

An increase in the capacity of athletic performance depends on adequate nutrition, which ensures optimal function of the musculoskeletal system, including tendon stability. However, little is known about the status of tendons and extracellular matrix modifications during malnutrition and nutritional recovery when leucine is used in response to exercise conditioning. The purpose of this study was to evaluate the collagen content and biomechanical aspects of the deep digital flexor tendon (DDFT) in malnourished rats submitted to nutritional recovery (control diet or leucine-rich diet) and aerobic physical activity. After 60 days of undernourishment (6% protein diet), the malnourished rats were subsequently nutritionally recovered with a control diet or leucine-rich diet and trained or not (swimming, without overload) for 5 weeks. The biomechanical analysis and quantification of hydroxyproline were assessed in the DDFT in all experimental groups. The leucine-rich diet increased hydroxyproline content in the tension region, independently of the training. In the compression region, hydroxyproline content was higher in the malnourished and leucine-trained groups. Biomechanical analysis showed a lower load in the malnourished and all-trained groups. The lowest stress was observed with control-trained animals. The nutritional-recovered groups showed higher strain values corresponding to control group, while the lowest values were observed in malnourished and trained groups. The results suggest that a leucine-rich diet stimulates collagen synthesis of the DDFT, especially when in combination with physical exercise, and seems to determine the increase of resistance and the biomechanical characteristics of tendons.
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http://dx.doi.org/10.1007/s00726-010-0810-1DOI Listing
January 2012

Oral administration of Aloe vera and honey reduces Walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue.

Phytother Res 2011 Apr 13;25(4):619-23. Epub 2010 Sep 13.

Laboratory of Nutrition and Cancer, Department of Anatomy, Cell Biology and Physiology and Biophysics, Institute of Biology, State University of Campinas -UNICAMP, Campinas, 13083970, São Paulo, Brazil.

Cancer is diagnosed in approximately 11 million people and is responsible for almost 8 million deaths worldwide every year. Research in cancer control has shown the importance of co-adjuvant therapies. Aloe vera may reduce tumour mass and metastasis rates, while honey may inhibit tumour growth. This study verified the influence of Aloe vera and honey on tumour growth and in the apoptosis process by assessing tumour size, the cell proliferation rate (Ki67-LI) and Bax/Bcl-2 expression at 7, 14 and 20 days after Walker 256 carcinoma implant in Wistar rats distributed into two groups: the WA group - tumour-bearing rats that received a gavage with a 670 µL/kg dose of Aloe vera and honey solution daily, and the CW group - tumour-bearing rats which received only a 0.9% NaCl solution. The effect of Aloe vera and honey against tumour growth was observed through a decrease in relative weight (%) and Ki67-LI in tumours from the WA group compared with those from the CW group. The Bax/Bcl-2 ratio increased in tumours from the WA group at all tested timepoints. These data suggest Aloe vera and honey can modulate tumour growth by reducing cell proliferation and increasing apoptosis susceptibility.
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http://dx.doi.org/10.1002/ptr.3293DOI Listing
April 2011

Leucine affects the fibroblastic Vero cells stimulating the cell proliferation and modulating the proteolysis process.

Amino Acids 2010 Jan 13;38(1):145-53. Epub 2008 Dec 13.

Laboratory of Nutrition and Cancer, Department of Physiology and Biophysics, Institute of Biology, State University of Campinas, UNICAMP, Campinas, Brazil.

Branched-chain amino acids, especially leucine, exert regulatory influences on protein and carbohydrate metabolism, ribosome biogenesis and gene expression. This study investigated the effects of leucine in fibroblastic cells analysing viability, proliferation, morphology, proteolysis enzymes activities and protein turnover. After exposure to culture medium enriched with 25 or 50 microM leucine for 24, 48 and 72 h, Vero cells have no alterations on viability and morphology. Leucine-treated cells showed increase on alkaline phosphatase activity and proliferation. The protein synthesis was slightly increased, whereas the protein degradation showed a deep reduction after leucine incubation. The chymotrypsin-like, cathepsin B and H and calpain activities were decreased in leucine-treated cells. In conclusion, the proteolytic pathways and the total protein degradation were modulated by leucine in Vero cells. Our observations support the concept that Vero cells may represent a new model for protein turnover study.
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http://dx.doi.org/10.1007/s00726-008-0222-7DOI Listing
January 2010

Reduction of hypothalamic protein tyrosine phosphatase improves insulin and leptin resistance in diet-induced obese rats.

Endocrinology 2008 Aug 8;149(8):3870-80. Epub 2008 May 8.

Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.

Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats.
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http://dx.doi.org/10.1210/en.2007-1506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2488223PMC
August 2008

Cancer during pregnancy alters the activity of rat placenta and enhances the expression of cleaved PARP, cytochrome-c and caspase 3.

BMC Cancer 2006 Jun 26;6:168. Epub 2006 Jun 26.

Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, CP 6109, 13083-970, SP, Brazil.

Background: The presence of cancer makes it difficult to predict the progress of pregnancy and can be deleterious to the maternal-foetal relationship. Apoptosis may affect a range of placental functions and result in the retardation of foetal growth. In this work, we investigated the placental alterations produced by tumour growth and the effects on the expression of apoptotic factors in placental tissue.

Methods: Adult female Wistar rats (90 days old, n = 54) were allocated to control (C), tumour-bearing (W), or ascitic fluid-injected (A) groups and were killed on the 16th, 19th or 21st day of pregnancy. Placental tissues were analysed using biochemical and histochemical assays.

Results: The placental protein content and glutathione-S-transferase activity were decreased in groups W and A. Histochemical analysis showed an increase in the number of cells with cleaved PARP, caspase 3 and cytochrome-c in groups W and A, indicating that the tumour growth clearly damaged placental tissue and affected the levels of apoptotic factors. These results were confirmed by western blotting.

Conclusion: Since trophoblastic cells are responsible for maintaining a normal placental function, the uncontrolled death of these cells in response to tumour cell growth or substances derived from ascitic fluid could have a negative impact on foetal development. Further knowledge of these events may help to preserve the foetus and placenta during development.
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http://dx.doi.org/10.1186/1471-2407-6-168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1534057PMC
June 2006

Cadmium chloride-induced oxidative stress in skeletal muscle cells in vitro.

Free Radic Biol Med 2005 Nov 1;39(10):1378-84. Epub 2005 Sep 1.

Departamento de Fisiologia e Biofísica e Departamento de Biologia Celular, Instituto de Biologia, Universidade Estadual de Campinas UNICAMP, CP 6109, 13083-970, Campinas, São Paulo, SP, Brazil.

The effects of cadmium chloride (CdCl(2)) on oxidative stress in the skeletal muscle cell line C(2)C(12) were investigated. Myoblast cells that differentiated into myotubes were treated with CdCl(2) (1, 3, 5, 7.5, 10, and 12.5 microM) for 24, 48, and 72 h. Subsequent assay of cell homogenates for MTT (3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide) reduction, neutral red uptake and nucleic acid content showed that cadmium was toxic to C(2)C(12) cells in a concentration-dependent manner. Glutathione-S-transferase activity (nmol microg of protein(-1) min(-1)) was increased with 1 and 3 microM CdCl(2) (36.9 +/- 5.6 and 32.1 +/- 6.0, respectively) compared to control cells (21.8 +/- 1.5), but decreased at higher concentrations (7.5 microM = 15.9 +/- 3.3, 10 microM = 15.9 +/- 4.6, and 12.5 microM = 10.5 +/- 2.8). An increase in malondialdehyde content (nmol microg of protein(-1)), especially at high CdCl(2) concentrations (control = 7.3 +/- 0.5; CdCl(2): 7.5 microM = 11.2 +/- 3.1, 10 microM = 14.6 +/- 3.8, and 12.5 microM = 20.5 +/- 6.5) indicated that there was enhanced lipid peroxidation. Light and scanning electron microscopy showed that there was a concentration-dependent loss of adherent cells and the formation of vesicles indicative of cell death. These results indicated that CdCl(2) increased oxidative stress in C(2)C(12) cells, and this stress probably compromised cell adhesion and the cellular antioxidant defense mechanisms.
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http://dx.doi.org/10.1016/j.freeradbiomed.2005.07.001DOI Listing
November 2005