Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features, despite some controversies in age-related studies. GDF11 has been poorly investigated in cancer, particularly in those with stemness capacity, such as hepatocellular carcinoma (HCC), one of the most aggressive cancers worldwide. Here, we focused on investigating the effects of GDF11 in liver cancer cells. GDF11 treatment significantly reduced proliferation, colony and spheroid formation in HCC cell lines. Consistently, down-regulation of CDK6, cyclin D1, cyclin A, and concomitant upregulation of p27 was observed after 24 h of treatment.Interestingly, cell viability was unchanged, but cell functionality was compromised. These effects were potentially induced by the expression of Ecadherin and Occludin, as well as Snail and N-cadherin repression, in a timedependent manner. Furthermore, GDF11 treatment for 72 h induced that cells were incapable of sustaining colony and sphere capacity in the absent of GDF11, up to 5 days, indicating that the effect of GDF11 on self-renewal capacity is not transient. Finally, in vivo invasion studies revealed a significant decrease in cell migration of hepatocellular carcinoma cells treated with GDF11 associated to a decreased proliferation judged by Ki67 staining. Data show that exogenous GDF11 displays tumor suppressor properties in HCC cells.

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Sarcopenia is a syndrome characterized by a progressive and generalized skeletal muscle mass and strength loss, as well as a poor physical performance, which as strongly been associated with aging. Sedentary lifestyle in the elderly contributes to this condition; however, physical activity improves health, reducing morbidity and mortality. Recent studies have shown that metformin (MTF) can also prevent muscle damage promoting muscular performance. To date, there is great controversy if MTF treatment combined with exercise training improves or nullifies the benefits provided by physical activity. This study is aimed at evaluating the effect of long-term moderate exercise combined with MTF treatment on body composition, strength, redox state, and survival rate during the life of female Wistar rats. In this study, rats performed moderate exercise during 20 of their 24 months of life and were treated with MTF for one year or for 6 months, i.e., from 12 to 24 months old and 18 to 24 months old. The body composition (percentage of fat, bone, and lean mass) was determined using a dual-energy X-ray absorption scanner (DXA), and grip strength was determined using a dynamometer. Likewise, medial and tibial nerve somatosensory evoked potentials were evaluated and the redox state was measured by HPLC, calculating the GSH/GSSG ratio in the gastrocnemius muscle. Our results suggest- that the MTF administration, both in the sedentary and the exercise groups, might activate a mechanism that is directly related to the induction of the hormetic response through the redox state modulation. MTF treatment does not eliminate the beneficial effects of exercise throughout life, and although MTF does not increase muscle mass, it increases longevity.

Acute pancreatitis is a multifactorial disease associated with profound changes of the pancreas induced by release of digestive enzymes that lead to increase in proinflammatory cytokine production, excessive tissue necrosis, edema, and bleeding. Elevated levels of hepatocyte growth factor (HGF) and its receptor c-Met have been observed in different chronic and acute pancreatic diseases including experimental models of acute pancreatitis. In the present study, we investigated the protective effects induced by the recombinant human HGF in a mouse model of cerulein-induced acute pancreatitis. Pancreatitis was induced by 8 hourly administrations of supramaximal cerulein injections (50 µg/kg, ip). HGF treatment (20 µg/kg, iv), significantly attenuated lipase content and amylase activity in serum as well as the degree inflammation and edema overall leading to less severe histologic changes such as necrosis, induced by cerulein. Protective effects of HGF were associated with activation of pro-survival pathways such as Akt, Erk1/2, and Nrf2 and increase in executor survival-related proteins and decrease in pro-apoptotic proteins. In addition, ROS content and lipid peroxidation were diminished, and glutathione synthesis increased in pancreas. Systemic protection was observed by lung histology. In conclusion, our data indicate that HGF exerts an Nrf2 and glutathione-mediated protective effect on acute pancreatitis reflected by a reduction in inflammation, edema, and oxidative stress.

Tumor cells utilize inappropriate epithelialmesenchymal transition (EMT) mechanisms during the invasive process. It is becoming increasingly clear that estradiol (E2) induces breast cancer cell progression and enhances EMT; however, the mechanisms associated with this are unclear. We investigated the role of E2 on the expression and intracellular localization of the tight junction (TJ)-associated proteins, zonula occluden 1 (ZO-1), ZO-1-associated nucleic acid binding (ZONAB), and occludin, on the activation of cSrc and human epidermal growth factor receptor 2 (HER2) expression and cellular migration in the estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. WeNovelty and Impact Statements We demonstrated that estrogen is able to induce tight junction (TJ) disruption in two breast cancer cell lines through the activation of c-Src. Ablated expression of the novel epithelial marker CRB3 could lead to increased cell migration. Based on our findings, we propose a novel estrogen-induced TJ pathway associated with breast cancer cell motility and, eventually, to metastasis. demonstrated that 1 nM E2 elicits c-Src activation after 15 min. The p-Src/ZO-1 complex led to ZO-1 and ZONAB disruption at the TJ and increased expression of HER2 mRNAs. These changes correlate with decreased expression of the epithelial markers occludin and CRB3 and increased synthesis of N-cadherin. This led to increased MCF-7 cell migration induced by E2, even in the presence of a cell proliferation inhibitor. Incubation with ICI 182,780 (Fulvestrant), an ER antagonist, precluded the effects of E2 on c-Src phosphorylation, p-Src/ZO-1 complex formation, ZO-1/ZONAB nuclear translocation, and migration of MCF-7 cells. Our findings suggest that E2 promotes TJ disruption during tumor progression and increases cell motility. We propose a novel pathway where estrogens promote EMTassociated mechanisms that possibly lead to metastasis.