Pioglitazone improves insulin sensitivity and reduces weight loss in Walker-256 tumor-bearing rats

Silva, Flaviane de Fatima; Ortiz‐Silva, Milene; Galia, Winny Beatriz de Souza; Cassolla, Priscila; Graciano, Maria Fernanda Rodrigues; Zaia, Cássia Thaïs Bussamra Vieira; Zaia, Dimas Augusto Morozin; Carpinelli, Ângelo Rafael; Silva, Francemilson Goulart da; Souza, Helenir Medri de

doi:10.1016/j.lfs.2016.12.016

Cited by 13 publications

(25 citation statements)

References 47 publications

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“…The W256 tumor‐bearing rat model has been previously used to study cancer‐induced cachexia. Cachexia was characterized by weight loss after tumor cell inoculation . Our results are consistent with previous studies.…”

Section: Discussionsupporting

confidence: 93%

Dynamic changes of urine proteome in a Walker 256 tumor‐bearing rat model

Guo

Gao

2017

Cancer Medicine

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Despite advances in cancer treatments, early diagnosis of cancer is still the most promising way to improve outcomes. Without homeostatic control, urine reflects systemic changes in the body and can potentially be used for early detection of cancer. In this study, a tumor‐bearing rat model was established by subcutaneous injection of Walker 256 cells. Urine samples from tumor‐bearing rats were collected at five time points during cancer development. Dynamic urine proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC‐MS/MS). Several urine proteins that changed at multiple time points were selected as candidate cancer biomarkers and were further validated by multiple reaction monitoring (MRM) analysis. It was found that the urinary protein patterns changed significantly with cancer development in a tumor‐bearing rat model. A total of 10 urinary proteins (HPT, APOA4, CO4, B2MG, A1AG, CATC, VCAM1, CALB1, CSPG4, and VTDB) changed significantly even before a tumor mass was palpable, and these early changes in urine could also be identified with differential abundance at late stages of cancer. Our results indicate that urine proteins could enable early detection of cancer at an early onset of tumor growth and monitoring of cancer progression.

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Section: Discussionsupporting

confidence: 93%

Dynamic changes of urine proteome in a Walker 256 tumor‐bearing rat model

Guo

Gao

2017

Cancer Medicine

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“…Therefore, the glucose produced by gluconeogenesis from glutamine and alanine must have been used as an energy source (anaerobic glycolysis) by the tumor. 45 As evidenced by the lower KITT (Figure 2), tumorbearing rats showed INS peripheral resistance, already observed in our studies, 5 which was not attenuated by any of the treatments. INS resistance in cancer has been associated with increased TNF-α, IL6, and FFA.…”

Section: Discussionsupporting

confidence: 75%

“…2 Lipolytic and proteolytic factors, such as lipid mobilizing factor (LMF), proteolysis-inducing factor (PIF), and proinflammatory cytokines (TNF-α, IL1, and IL6), play a central role in the development of metabolic alterations of cachexia. 1,2,4 However, hypoinsulinemia and insulin (INS) resistance, often present in cancer-bearing, [5][6][7][8][9][10] also appear to contribute to the metabolic changes of cachexia, since INS exerts important anabolic and anticatabolic effects in the metabolism of lipids, proteins and carbohydrates. Hypoinsulinemia related to cancer is caused by decreased secretion of INS by β-cells, 5,6,11 while INS resistance is attributed to the increase of cytokines (TNF-α and IL6) and free fatty acids (FFA) resulting from intense lipolysis.…”

Section: Introductionmentioning

confidence: 99%

“…16 Thus, it is possible that treatments that prevent the hypoinsulinemia and/or INS resistance may attenuate the decreased Akt phosphorylation (p-Akt) and consequently the loss of adipose, muscular and corporeal mass (cachexia). However, few studies have evaluated the effects of INS 7,[18][19][20][21] and INS sensitizing agent 5,6,8 on p-Akt and other proteins related to INS resistance, affected by the tumor. We recently found that treatments of Walker-256 tumor-bearing rats with advanced cachexia, which exhibit adipose and muscle mass loss [22][23][24][25][26] hypoinsulinemia and INS resistance, 5,6 with INS sensitizer antidiabetics (metformin or pioglitazone), isolated or combined with low dose of INS, were unable to attenuate the INS resistance and metabolic changes.…”

Section: Introductionmentioning

confidence: 99%

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Akt activation by insulin treatment attenuates cachexia in Walker‐256 tumor‐bearing rats

Silva

Morais

Silva

et al. 2020

J of Cellular Biochemistry

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Cancer‐bearing often exhibits hypoinsulinemia, insulin (INS) resistance and glutamine depletion associated with cachexia. However, INS and glutamine effects on cachexia metabolic abnormalities, particularly on tumor‐affected proteins related to INS resistance, are poorly known. The main purpose of this study was to investigate the effects of INS and glutamine dipeptide (GDP) treatments on phospho‐protein kinase B (p‐Akt), and phospho‐hormone sensitive lipase (p‐HSL) in Walker‐256 tumor‐bearing rats. INS (NPH, 40 UI/kg, subcutaneous), GDP (1.5 g/kg, oral), INS+GDP or vehicle (control rats) were administered for 13 days, once a day, starting at the day of inoculation of tumor cells. The experiments were performed 4 hours after the last treatment to evaluate acute effects of INS and GDP, besides the chronic effects. INS and/or INS+GDP treatments, which markedly increased the insulinemia, increased the p‐Akt: total Akt ratio and prevented the increased p‐HSLSer552: total HSL ratio in the retroperitoneal fat of tumor‐bearing rats, without changing the INS resistance and increased expression of factor tumor necrosis‐α (TNF‐α) in this tissue. INS and INS+GDP also increased the p‐Akt: total Akt ratio, whereas GDP and INS+GDP increased the GLUT4 glucose transporter gene expression, in the gastrocnemius muscle of the tumor‐bearing rats. Accordingly, treatments with INS and INS+GDP markedly reduced glycemia, increased retroperitoneal fat and attenuated the body mass loss of tumor‐bearing rats. In conclusion, hyperinsulinemia induced by high‐dose INS treatments increased Akt phosphorylation and prevented increased p‐HSLSer552: total HSL ratio, overlapping INS resistance. These effects are consistent with increased fat mass gain and weight loss (cachexia) attenuation of tumor‐bearing rats, evidencing that Akt activation is a potential strategy to prevent loss of fat mass in cancer cachexia.

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“…The W256 tumor-bearing rat model has been previously used to study cancer-induced cachexia. Cachexia was characterized by weight loss after tumor cell inoculation [109,110] . This study also demonstrated results consistent with previous studies ( Fig.…”

Section: Functional Analysis Of Differential Proteinsmentioning

confidence: 99%

Early changes in the urine proteome in a rat liver tumor model

Zhang

Gao

2019

Preprint

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Urine, as a potential biomarker source among the body fluids, can accumulate many changes in the body due to the lack of a mechanism to maintain a homeostatic state. Previous studies have demonstrated that proteomic technology can find many potential biomarkers to reflect different diseases in the urine.This study aims to detect early changes in the urinary proteome in a rat liver tumor model. The tumor model was established with the Walker-256 carcinosarcoma cell line (W256). Compared to before the injection, ninety-five differential proteins were significantly changed in the experimental rats. At day 3, twelve proteins were identified in the absence of pathological changes, and four of them were altered at all four time-points (B2MG, VCAM1, HA11, and LG3BP). Seven had previously been associated with liver cancer. At day 5, fifty-two differential proteins were identified. At day 7 and day 11, there was a significant decrease in the body weight of the rats, and tumor tissue was observed in the liver. Fifty-two and forty differential proteins were changed significantly at day 7 and day 11, respectively. Of the proteins that were identified at these three time-points, and twenty-four were reported to be associated with liver cancer. Comparing the differential urinary proteins and biological processes of liver tumor model with those in different models of W256 grown in other organs, specific differential protein patterns were found among the four models, which indicates that the differential urinary proteins can reflect the differences when the same tumor cell grown in different organs.Significance: This study demonstrated that (1) the rat liver tumor model caused early changes in urinary proteins may give new insight into the early diagnosis of liver cancer; (2) the same tumor cell grown in different organs can be reflected in differential urinary proteins.All rats were housed under a standard 12-h light/12-h dark cycle, and the room temperature and humidity were maintained at a standard level (22 ± 1 °C, 65-70%). Tumor cell line and CultureWalker 256 tumor cells were cultured in the ascitic fluid of Wistar rats. All cells were harvested from the rats who were given an intraperitoneal injection of 107 Walker 256 carcinoma cells after two cycles of 7 d cell passage. Then, W256 cells were resuspended in phosphate-buffered saline (PBS) before injection. The viability of the cells was detected by the Trypan blue exclusion test using a Neubauer chamber. Rat models of liver cancerA tumor-bearing animal model was established in this study. All Wistar rats were randomly divided into different groups: the control group (n =5), and the Walker-256 (W256) tumor-bearing group (n =12).After anesthesia, the left medial lobe of the liver was exposed. W256 cells (2.5× 10 5 ) were visually injected under the hepatic capsule into this lobe. The injection volume is 0.1 ml. An equal volume of PBS was also injected into the same location of the control rats. Histological analysisIn the W256 model, the livers of the experimental and cont...

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Pioglitazone improves insulin sensitivity and reduces weight loss in Walker-256 tumor-bearing rats

Cited by 13 publications

References 47 publications

Dynamic changes of urine proteome in a Walker 256 tumor‐bearing rat model

Dynamic changes of urine proteome in a Walker 256 tumor‐bearing rat model

Akt activation by insulin treatment attenuates cachexia in Walker‐256 tumor‐bearing rats

Early changes in the urine proteome in a rat liver tumor model

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