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

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 20th 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 growth16CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP302863/2013-32010/00209-9; 2011/08276-0; 2013/16115-

The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling

SARS-CoV-2 nonstructural protein 3 (Nsp3) contains a macrodomain that is essential for coronavirus pathogenesis and is thus an attractive target for drug development. This macrodomain is thought to counteract the host interferon (IFN) response, an important antiviral signalling cascade, via the reversal of protein ADP-ribosylation, a posttranslational modification catalyzed by host poly(ADP-ribose) polymerases (PARPs). However, the main cellular targets of the coronavirus macrodomain that mediate this effect are currently unknown. Here, we use a robust immunofluorescence-based assay to show that activation of the IFN response induces ADP-ribosylation of host proteins and that ectopic expression of the SARSCoV- 2 Nsp3 macrodomain reverses this modification in human cells. We further demonstrate that this assay can be used to screen for on-target and cell-active macrodomain inhibitors. This IFN-induced ADP-ribosylation is dependent on PARP9 and its binding partner DTX3L, but surprisingly the expression of the Nsp3 macrodomain or the deletion of either PARP9 or DTX3L does not impair IFN signaling or the induction of IFNresponsive genes. Our results suggest that PARP9/DTX3Ldependent ADP-ribosylation is a downstream effector of the host IFN response and that the cellular function of the SARSCoV- 2 Nsp3 macrodomain is to hydrolyze this end product of IFN signaling, rather than to suppress the IFN response itself

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, [10]-gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients

Effects of Aloe vera and honey on tumor growth evolution in rats

Orientador: Maria Cristina Cintra Gomes MarcondesDissertação (mestrado) - Universidade Estadual de Campinas,I nstituto de Bi9ologiaResumo: O câncer é responsável pela morte de oito milhões de pessoas todos os anos, sendo que anualmente são diagnosticados mais de onze milhões de novos casos. O estudo de tratamentos alternativos e coadjuvantes é, portanto, de grande valia. Aventa-se que tanto Aloe vera quanto o mel contém efeitos anti-câncer. O objetivo deste trabalho foi verificar a ação do homogeneizado de Aloe vera e mel sobre o crescimento tumoral e caquexia em ratos Wistar portadores de carcinossarcoma de Walker 256. Visando avaliar o impacto da administração de Aloe vera e mel sobre a proliferação celular e apoptose no decorrer do desenvolvimento tumoral, foram coletados tecido hepático e tumoral de animais sacrificados após 7, 14 e 20 dias de implantação tumoral. As análises imunohistoquímicas de tumores provenientes de animais tratados com homogeneizado de Aloe vera e mel revelaram, ao longo do desenvolvimento tumoral, queda na taxa de proliferação celular (Ki-67) e aumento na susceptibilidade à apoptose (relação Bax/Bcl-2) além de menor peso relativo do tumor, quando comparados aos tumores de animais que receberam soro fisiológico. Paralelamente, a análise do tecido hepático desses animais mostrou queda na susceptibilidade à apoptose (relação Bax/Bcl-2) em relação aos animais que não foram tratados com Aloe vera e mel. A fim de se avaliar o efeito terapêutico do homogeneizado de Aloe vera e mel sobre parâmetros relacionados ao estresse oxidativo e à caquexia, ratos Wistar tratados ou não anteriormente à indução tumoral foram redistribuídos de forma a iniciar (CWA), interromper (AW), manter (AWA) ou não receber tratamento (CW) com Aloe vera e mel após a indução de tumor. Os animais foram monitorados quanto ao ganho de peso, consumo de dieta e peso calculado do tumor. Após 21 dias de evolução tumoral, as análises morfométricas associadas à quantificação de proteínas séricas, bem como avaliação de estresse oxidativo (envolvendo análise da atividade de catalase, superoxido dismutase, glutationa S tranferase e fostatase alcalina, além do teor de proteína e MDA), em órgãos como fígado, músculo e coração, sugerem que o tratamento com homogeneizado de Aloe vera e mel auxiliou na modulação do estresse oxidativo, espoliação e caquexia, especialmente quando administrado de forma terapêutica (CWA). Em contrapartida, foi observada tendência a estresse oxidativo bem como queda na atividade de enzimas antioxidantes no tecido tumoral, em animais tratados com Aloe vera e mel. Os dados obtidos sugerem que a administração de Aloe vera e mel preserva a integridade dos tecidos hospedeiros enquanto provoca detrimento do tecido tumoralAbstract: Cancer is diagnosed in approximately 11 million people and is responsible for approximately 8 million deaths 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 cachexia in tumour-bearing rats. The influence of Aloe vera and honey on tumour growth evolution was assessed through tumour cell proliferation rate (Ki67-LI) and Bax/Bcl-2 ratio at 7, 14 and 20 days after the implant of Walker 256 carcinoma (sc) in adult rats. The effect of Aloe vera and honey against tumour growth was observed through a decrease in tumour cell proliferative rates and an increase in apoptosis susceptibility (Bax/Bcl-2 ratio) in tumours of treated group compared to untreated group. In contrast, it was observed a decrease in apoptosis susceptibility (Bax/Bcl-2 ratio) in livers of Aloe vera and honey-treated group, showing a possible protective effect in liver tissue. In order to elucidate the therapeutic effects of Aloe vera and honey solution on oxidative stress and cachexia development, Aloe vera and honey-treated and untreated rats before tumour induction were distributed into the following groups: tumour-bearing rats treated after tumour implant (CWA), treated before tumour implant (AW), treated before and after tumour implant (AWA) with Aloe vera and honey solution and untreated tumour-bearing rats (CW). After 21 days of tumour implant, morphometric analyses, serum proteins content and oxidative stress assays (catalase, superoxide dismutase, glutathione-Stransferase, alkaline phosphatase activities and protein and MDA content) were evaluated in liver, muscle and myocardium. The Aloe vera and honey treatment modulated oxidative stress, tissue wasting and cachexia, especially as therapeutic way (CWA). On the other hand, tumour of Aloe vera and honey-treated rats tended to increase oxidative stress and/or decrease antioxidant enzymes activities. These data suggested Aloe vera and honey treatment affected tumour and host in a different way, by preserving host tissues while promoted damages in tumour tissueMestradoFisiologiaMestre em Biologia Funcional e Molecula

Vide for Maade by af Jerne sogn

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)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).181011281135Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2010/00209-9, 2013/16115-1]CNPq [304604/2010-0, 302863/2013-3]FAPESP [2007/05788-4, 2010/00714-5

An In Vivo Shrna Screen For Breast Cancer Metastasis Suppressor Genes

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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.

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).181128-113

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

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 21days 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 process75577586CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP302863/2013-3sem informação2010/00714-5; 2010/00209-9; 2009/11993-5; 2013/16115-