In silico design and cell-based evaluation of two dual anti breast cancer compounds targeting Bcl-2 and GPER.

According to WHO statistics, breast cancer (BC) disease represents about 2.3 million diagnosed and 685,000 deaths globally. Regarding histological classification of BC, the Estrogen (ER) and Progesterone (PR) receptors negative-expression cancer, named Triple-Negative BC (TNBC), represents the most aggressive type of this disease, making it a challenge for drug discovery. In this context, our research group, applying a well-established Virtual Screening (VS) protocol, in addition to docking and molecular dynamics simulations studies, yielded two ligands identified as 6 and 37 which were chemically synthesized and evaluated on MCF-7 and MDA-MB-231 cancer cell lines. Strikingly, 37 assayed on MDA-MB-231 (a TNBC cell model) depicted an outstanding value of 18.66 µM much lower than 65.67 µM yielded by Gossypol Bcl-2 inhibitor whose main disadvantage is to produce multiple toxic effects. Highlighted above, enforce the premise of the computational tools to find new therapeutic options against the most aggressive forms of breast cancer, as the results herein showed.

A moderate intensity exercise program improves physical function and oxidative damage in older women with and without sarcopenic obesity.

BACKGROUND AND OBJECTIVES: The excess of body fat and muscle mass loss in adulthood results in sarcopenic obesity, which is associated with disability and poor physical condition. A relationship among obesity, sarcopenia and oxidative stress also has been established. These aspects limit a good muscle function which is crucial in the independence of older women with and without sarcopenic obesity. This study had as objective to design a moderate intensity exercise program for older women with sarcopenic obesity, and to examine its effects on oxidative damage and physical function. We hypothesized that the exercise program will reduce oxidative damage and to improve the physical function of older women with sarcopenic obesity. METHODS: Thirty healthy women (68 ± 5.05 years old) and 30 women with sarcopenic obesity (68.06 ± 5.75 years old) from the Integral Development of the Family rest home participated in the evaluation. The participants underwent evaluations of body composition, physical fitness (timed up-and-go [TUG] test, reaction time, gait speed, flexibility and muscle strength) and oxidative stress (oxidative damage to lipid and protein as well as evaluation of the antioxidant system) before and after of moderate intensity exercise program. The program consisted of warm-up, flexibility; aerobic exercises of moderate intensity (VO2 max and HR max between 60% and 70%); isotonic exercises of low intensity with progressive weight (250 g of initial weight, with increase every two weeks until reaching 750 g of final weight) and global stretching at the end of each section. The program was monitored on a personal basis and undertaken three times a week over three months. RESULTS: In both groups, the program induced a five-fold increase in muscle strength, an increase in flexibility and improvement of fragility parameters (TUG and gait speed) (P ≤ 0.001, respectively). Furthermore, this exercise program decreased oxidative damage and increased antioxidant defense (P ≤ 0.001) to a greater extent in the sarcopenic group. CONCLUSION: It was concluded that moderate intensity exercise is an effective approach to promote changes in body composition, physical fitness and to reduce oxidative damage in older women with and without sarcopenic obesity. These findings might have important implications for the prevention or treatment of sarcopenic obesity in older people.

Synthesis and In Vitro Evaluation of Tetrahydroquinoline Derivatives as Antiproliferative Compounds of Breast Cancer via Targeting the GPER.

BACKGROUND: Some reports have demonstrated the role of the G Protein-coupled Estrogen Receptor (GPER) in growth and proliferation of breast cancer cells. OBJECTIVE: In an effort to develop new therapeutic strategies against breast cancer, we employed an in silico study to explore the binding modes of tetrahydroquinoline 2 and 4 to be compared with the reported ligands G1 and G1PABA. METHODS: This study aimed to design and filter ligands by in silico studies determining their Lipinski's rule, toxicity and binding properties with GPER to achieve experimental assays as anti-proliferative compounds of breast cancer cell lines. RESULTS: In silico studies suggest as promissory two tetrahydroquinoline 2 and 4 which contain a carboxyl group instead of the acetyl group (as is needed for G1 synthesis), which add low (2) and high hindrance (4) chemical moieties to explore the polar, hydrophobic and hindrance effects. Docking and molecular dynamics simulations of the target compounds were performed with GPER to explore their binding mode and free energy values. In addition, the target small molecules were synthesized and assayed in vitro using breast cancer cells (MCF-7 and MDA-MB-231). Experimental assays showed that compound 2 decreased cell proliferation, showing IC50 values of 50µM and 25µM after 72h of treatment of MCF-7 and MDA-MB-231 cell lines, respectively. Importantly, compound 2 showed a similar inhibitory effect on proliferation as G1 compound in MDA-MB-231 cells, suggesting that both ligands reach the GPER-binding site in a similar way, as was demonstrated through in silico studies. CONCLUSION: A concentration-dependent inhibition of cell proliferation occurred with compound 2 in the two cell lines regardless of GPER.

Preeclampsia is associated with ACE I/D polymorphism, obesity and oxidative damage in Mexican women.

OBJECTIVE: This study sought to determine whether the angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism, obesity and oxidative damage are risk factors for the development of preeclampsia in Mexican women. STUDY DESIGN: A total of 66 women with preeclampsia (PE) and 37 women with normal pregnancies (NP) were included in the study. DNA was extracted from whole blood, and the ACE I/D polymorphism was evaluated by polymerase chain reaction. ACE activity and oxidative damage were assessed in plasma. The intergroup comparisons were analyzed by an analysis of variance (ANOVA) with post hoc tests. Hardy-Weinberg equilibrium (HWE) was tested by x2 analysis, odds ratios (OR) were calculated as a measure of the degree of relative risk of preeclampsia, and for correlations, we used Spearman's correlation coefficient. RESULTS: The frequency of the DD genotype was higher in PE (34.84%) than NP (10.82%). The OR of the DD genotype and D allele were associated with a 4.4-fold (CI=95% 2.24-14) and 3-fold (CI=95% 1.69-5.62) increased risk of developing PE, respectively. Major ACE activity in the DD genotype and obesity were features of the PE group; oxidative damage to proteins and a reduction in the activity of the antioxidant system showed a correlation with BMI (p<0.01). CONCLUSION: Our results suggest that ACE I/D polymorphism, high ACE activity, body mass index and oxidative damage may play key roles in the pathogenesis of PE in the Mexican population. Furthermore, these findings could be used as predictive factors of PE.

An association of cocoa consumption with improved physical fitness and decreased muscle damage and oxidative stress in athletes.

BACKGROUND: Several studies have demonstrated the protective effects of cocoa consumption, due to its anti-inflammatory and antioxidant properties. Acute exercise induces oxidative stress and causes muscular damage during training. This study was designed to examine the effect of cocoa consumption on the markers of muscle damage, oxidative stress and physical fitness in professional soccer players. METHODS: Fifteen players (15-18 years old) were included in the study. Biochemical parameters, markers of muscle damage and oxidative stress, and physical performance were evaluated before and after cocoa consumption. Biochemical parameters determined the healthy metabolic status of the study group; biomarkers of muscle and oxidative damage were measured in blood to establish muscle and redox status. RESULTS: However, high levels of biomarkers of muscle damage were detected. Interestingly, cocoa consumption decreased the muscle damage biomarkers of CK and LDH by 39.4% and 23.03%, respectively. The redox status was modified by a decrease in oxidative damage (carbonyl groups, 26.31%; thiol groups, 27.52%; MDA, 32.42%) and an increase in total antioxidant capacity (15.98%) and GSH-Px activity (26.37%). In addition, we observed an increase in physical performance by 4% in the Cooper Test. CONCLUSIONS: Our findings suggest that a short period of cocoa consumption could be useful in maintaining a good physical fitness, due to the favourable effects on muscle and redox status in athletes during exhaustive exercise.

The association of subtypes of breast cancer with tumour characteristics and reproductive factors in 1326 Mexican women.

AIM OF THE STUDY: In breast cancer, oestrogen receptor (ER), progesterone receptor (PgR), and HER2 (HER2/Neu) expression status are used to classify neoplasms into subtypes: Luminal A, Luminal B, HER2/Neu type, and Basallike. The aim of the present study was to establish the molecular subtypes of breast cancers and their association with tumour characteristics and reproductive factors in Mexican women. MATERIAL AND METHODS: A total of 1326 biopsies of breast tumour tissues were analysed for ER, PR, and HER2/Neu by immunohistochemistry (IHC). Information regarding age, tumour characteristics, and node involvement profiles were collected. RESULTS: IHC established that the most common subtype of breast cancer was Luminal A (64.93%), followed by Basal-Like (13.88%), Luminal B (12.52%), and HER2/Neu (8.67%). T2-size tumours (> 2 cm but < 5 cm) were present in 47.59% of all patients. Univariate analysis showed that lymph node positivity (p = 0.009), stage (p = 0.013), and placement of the tumour (p = 0.001) were factors associated with breast cancer subtype. CONCLUSIONS: Our data show that IHC is useful for distinguishing different subtypes of breast cancer and that Luminal A is the most common breast cancer subtype in the Mexican population. All subtypes were associated with unfavourable clinicopathological features, suggesting that late diagnosis is an important contributor to high mortality rates in the Mexican population.

Arginase activity in patients with breast cancer: an analysis of plasma, tumors, and its relationship with the presence of the estrogen receptor.

BACKGROUND: Breast cancer is an important cause of cancerrelated death in women. In this pathological condition, arginase plays a role by providing ornithine as a substrate for the biosynthesis of polyamines which are important in tumor progression. The aim of this work was to determine the arginase activity in the plasma and tumors of patients with breast cancer; also, we investigated the relationship between this activity and the presence of the estrogen receptor. PATIENTS AND METHODS: We evaluated the plasma arginase activity levels in 80 women with breast cancer and 42 healthy control subjects. We also measured the arginase levels in 42 breast cancer biopsies and 42 control tissues. RESULTS: The mean activity of arginase in plasma was higher in breast cancer patients (0.78 nM/min/mg protein ± 0.04; p = 0.001) than in healthy volunteers (0.53 nM/ min/mg protein ± 0.04); however, this difference was indicative of patients in the advanced stages of the disease (n = 38, stage III; p < 0.0001). In addition, we did not find a relationship between the estrogen receptor and arginase activity. CONCLUSION: Our results show a higher arginase activity in the plasma of patients in the advanced stages of the disease, suggesting that arginase activity could serve as a possible biological marker of breast cancer progression.

Chemical and functional changes of human insulin by in vitro incubation with blood from diabetic patients in oxidative stress.

Oxidative stress damage to biomolecules has been implicated in several diseases including diabetes mellitus. In the present study, we investigated the effect of oxidative stress in whole blood (WB) from diabetic patients (n = 60) on recombinant human insulin. Insulin was incubated with WB obtained from diabetic patients (DP) who had hyperglycemia (>300 mg/dL) or from 41 healthy volunteers (HV). Whole blood of DP, unlike WB of HV, induced higher values of formazan (142%), dityrosines (279%), and carbonyls (58%) in the insulin residues. Interestingly, the insulin modified by WB of DP showed less hypoglycemic activity in rat (30%) in comparison with insulin incubated with WB of HV. The incubation of insulin in WB from DP induces chemical changes in insulin and a decrease in its biological activity, events that might be associated with the high levels of oxidative stress markers found in the plasma of these patients.