Ageing is a complex process characterized mainly by a decline in the function of cells, tissues, and organs, resulting in an increased risk of mortality. This process involves several changes, ...described as hallmarks of ageing, which include genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell depletion, and altered intracellular communication. The determining role that environmental factors such as diet and lifestyle play on health, life expectancy, and susceptibility to diseases, including cancer and neurodegenerative diseases, is wellestablished. In view of the growing interest in the beneficial effects of phytochemicals in the prevention of chronic diseases, several studies have been conducted, and they strongly suggest that the intake of dietary polyphenols may bring numerous benefits due to their antioxidant and anti-inflammatory properties, and their intake has been associated with impaired ageing in humans. Polyphenol intake has been shown to be effective in ameliorating several age-related phenotypes, including oxidative stress, inflammatory processes, impaired proteostasis, and cellular senescence, among other features, which contribute to an increased risk of ageing-associated diseases. This review aims to address, in a general way, the main findings described in the literature about the benefits of polyphenols in each of the hallmarks of ageing, as well as the main regulatory mechanisms responsible for the observed antiageing effects.
Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Statins are well-tolerated, inexpensive, and widely prescribed ...as cholesterol-lowering agents to treat hyperlipidemia and to prevent cardiovascular diseases through the blockage of the mevalonate metabolic pathway. These drugs have also shown promising anti-cancer activity through pleiotropic effects including the induction of lymphoma cell death. However, their potential use as anti-MCL agents has not been evaluated so far.
The present study aimed to investigate the activity of simvastatin on MCL cells.
We evaluated the cytotoxicity of simvastatin in MCL cell lines by CellTiter-Glo and lactate dehydrogenase (LDH) release assays. Cell proliferation and mitotic index were assessed by direct cell recounting and histone H3-pSer10 immunostaining. Apoptosis induction and reactive oxygen species (ROS) generation were evaluated by flow cytometry. Cell migration and invasion properties were determined by transwell assay. The antitumoral effect of simvastatin in vivo was evaluated in a chick embryo chorioallantoic membrane (CAM) MCL xenograft model.
We show that treatment with simvastatin induced a 2 to 6-fold LDH release, inhibited more than 50% of cell proliferation, and enhanced the caspase-independent ROS-mediated death of MCL cells. The effective impairment of MCL cell survival was accompanied by the inhibition of AKT and mTOR phosphorylation. Moreover, simvastatin strongly decreased MCL cell migration and invasion ability, leading to a 55% tumor growth inhibition and a consistent diminution of bone marrow and spleen metastasis in vivo.
Altogether, these data provide the first preclinical insight into the effect of simvastatin against MCL cells, suggesting that this agent might be considered for repurpose as a precise MCL therapy.
BACKGROUND : Although endoscopic vacuum therapy (EVT) has been successfully used to treat postoperative upper gastrointestinal (UGI) wall defects, its use demands special materials and several ...endoscopic treatment sessions. Herein, we propose a technical modification of EVT using a double tube (tube-in-tube drain) without polyurethane sponges for the drainage element. The tube-in-tube drainage device enables irrigation and application of suction. A flowchart for standardizing the management of postoperative UGI wall defects with this device is presented. METHODS : An EVT modification was made to achieve frequent fistula cleansing, with 3 % hydrogen peroxide rinsing, and the application of negative pressure. A tube-in-tube drain without polyurethane sponges can be inserted like a nasogastric tube or passed through a previously positioned surgical drain. This was a retrospective two-center observational study, with data collected from 30 consecutive patients. Technical success, clinical success, adverse events, time under therapy, interval time from procedure to fistula diagnosis and treatment start, size of transmural defect, volume of cavity, number of endoscopic treatment sessions, and mortality were reviewed. RESULTS : 30 patients with UGI wall defects were treated. The technical and clinical success rates were 100 % and 86.7 %, respectively. Three patients (10 %) had adverse events and three patients (10 %) died. The median time under therapy was of 19 days (range 1-70) and the median number of endoscopic sessions was 3 (range 1-9). CONCLUSIONS : This standardized approach and EVT modification using a tube-in-tube drain, with frequent fistula cleansing, were successful and safe in a wide variety of UGI wall defects.
Background
GATA factors, which constitute a family of transcription regulatory proteins, participate in gastrointestinal development. Trefoil factor 1 (
TFF1
) plays a crucial role in mucosal defense ...and healing, and evidence suggests that
GATA
-
5
mediated its regulation. Gastric cancer is a multiple-step process triggered by
Helicobacter pylori
and is characterized by accumulation of molecular and epigenetic alteration. The aim of this study was to evaluate the effect of
H. pylori
infection on the regulation of
GATA
-
5
and
TFF1
in vitro and in vivo.
Results
Infected cells exhibited upregulation of
GATA
-
5
and
TFF1
after 48 h. An increase in
GATA
-
5
and
TFF1
mRNA levels was also found in mice samples after 6 and 12 months of infection, respectively. In human samples, we found an association between
H. pylori
infection and
GATA
-
5
upregulation. In fact, among
H. pylori
-infected patients, hypermethylation was observed in 45.5% of pediatric samples, in 62.6% of chronic gastritis samples, and in 63% of gastric cancer samples. Regarding
TFF1
, the expression levels were similar in pediatrics and adults patients, and were independent of
H. pylori
infection, and the expression of these factors was downregulated in gastric cancer samples.
GATA
-
5
promoter methylation was associated with a decrease in
TFF1
mRNA levels.
Conclusions
Our results suggest that the upregulation of
GATA
-
5
and
TFF1
observed in vitro and in vivo may be correlated with a protective effect of the mucosa in response to infection. The epigenetic inactivation of
GATA
-
5
observed in human biopsies from infected patients may suggest that this alteration is an early event occurring in association with
H. pylori
infection.
The aim of this study was to evaluate the effects of guarana on mitochondrial biogenesis in a high-fat diet (HFD)-fed mice. C57BL6J mice were divided in two groups: high-fat diet HFD and high-fat ...diet + guarana (HFD-GUA). Both groups received HFD and water ad libitum and the HFD-GUA group also received a daily gavage of guarana (1 g/kg weight). Body weight and food intake was measured weekly. Glycemic, triglyceride, and cholesterol levels were determined. VO₂ and energy expenditure (EE) were determined by indirect calorimetry. Gene expression was evaluated by real-time PCR and protein content by western blotting. The HFD-GUA group presented lower body weight, subcutaneous, retroperitoneal, visceral, and epididyimal adipose tissue depots, and glycemic and triglyceride levels, with no change in food intake and cholesterol levels. Furthermore, the HFD-GUA group presented an increase in VO₂ and basal energy expenditure (EE), as well as
α,
,
,
,
, and
expression in the muscle and brown adipose tissue. In addition, the HFD-GUA group presented an increase in mtDNA (mitochondrial deoxyribonucleic acid) content in the muscle when compared to the HFD group. Thus, our data showed that guarana leads to an increase in energetic metabolism and stimulates mitochondrial biogenesis, contributing to control of weight gain, even when associated with high-fat diet.
Parkinson's disease (PD) is characterized by a range of motor signs, but cognitive dysfunction is also observed. Supplementation with folic acid and vitamin B12 is expected to prevent cognitive ...impairment. To test this in PD, we promoted a lesion within the substantia nigra
of rats using the neurotoxin rotenone. In the sequence, the animals were supplemented with folic acid and vitamin B12 for 14 consecutive days and subjected to the object recognition test. We observed an impairment in object recognition memory after rotenone administration, which was prevented by supplementation (
< 0.01). Supplementation may adjust gene expression through efficient DNA methylation. To verify this, we measured the expression and methylation of the kynureninase gene (
), whose product metabolizes neurotoxic metabolites often accumulated in PD as kynurenine. Supplementation prevented the decrease in
expression induced by rotenone in the substantia nigra (
< 0.05), corroborating the behavioral data. No differences were observed concerning the methylation analysis of two CpG sites in the
promoter. Instead, we suggest that folic acid and vitamin B12 increased global DNA methylation, reduced the expression of
inhibitors, maintained Kynu-dependent pathway homeostasis, and prevented the memory impairment induced by rotenone. Our study raises the possibility of adjuvant therapy for PD with folic acid and vitamin B12.
Although the classification of breast carcinomas into molecular or immunohistochemical subtypes has contributed to a better categorization of women into different therapeutic regimens, breast cancer ...nevertheless still progresses or recurs in a remarkable number of patients. Identifying women who would benefit from chemotherapy could potentially increase treatment effectiveness, which has important implications for long-term survival. Metabolomic analyses of fluids and tissues from cancer patients improve our knowledge of the reprogramming of metabolic pathways involved in resistance to chemotherapy. This review evaluates how recent metabolomic approaches have contributed to understanding the relationship between breast cancer and the acquisition of resistance. We focus on the advantages and challenges of cancer treatment and the use of new strategies in clinical care, which helps us comprehend drug resistance and predict responses to treatment.
Abstract
Self-expanding metallic stents (SEMS) are considered the treatment of choice for the palliation of dysphagia and fistulas in inoperable esophageal neoplasms. However, the safety of SEMSs in ...patients who received or who will be submitted to radiotherapy (RT) is uncertain. The study aimed to evaluate the impact of RT on adverse events (AEs) in patients with esophageal cancer with SEMSs. This is a retrospective study conducted at a tertiary cancer hospital from 2009 to 2018. We collected information regarding RT, the histological type of the tumor, the model of SEMSs and AEs after stent placement. Three hundred twenty-three patients with malignant stenosis or fistula were treated with SEMSs. The predominant histological type was squamous cell carcinoma (79.6%). A total of 282 partially covered and 41 fully covered SEMSs were inserted. Of the 323 patients, 182 did not received RT, 118 received RT before SEMS placement and 23 after. Comparing the group that received RT before stent insertion with the group that did not, the first one presented a higher frequency of severe pain (9/118 7.6% vs. 3/182 1.6%; P = 0.02). The group treated with RT after stent placement had a higher risk of global AEs (13/23 56.5% vs. 63/182 34.6%; P = 0.019), ingrowth/overgrowth (6/23 26.1% vs. 21/182 11.5%; P = 0.045) and gastroesophageal reflux (2/23 8.7% vs. 2/182 1.1%; P = 0.034). Treatment with RT before stent placement in patients with inoperable esophageal neoplasm prolongs survival and is associated with an increased risk of severe chest pain. Treatment with RT of patients with an esophageal stent increases the frequency of minor, not life-threatening AEs.
For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by ...immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.
Malignant esophagorespiratory fistulas (MERFs) usually are managed by the placement of self-expandable metal stents (SEMSs) but with conflicting results. This study aimed to identify risk factors ...associated with clinical failure after SEMS placement for the treatment of MERFs.
This was a retrospective analysis of a prospectively maintained database used at a tertiary-care cancer hospital, with patients treated with SEMS placement for MERFs between January 2009 and February 2016. Logistic regression was used to identify predictive factors for clinical outcomes and to estimate the odds ratio (OR) and the 95% confidence interval (CI). The Kaplan-Meier method was used for survival analysis, and comparisons were made by using the log-rank test.
A total of 71 patients (55 male, mean age 59 years) were included in the study, and 70 were considered for the final analysis (1 failed stent insertion). Clinical failure occurred in 44% of patients. An Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4 and fistula development during esophageal cancer treatment were associated with an increased risk of clinical failure. ECOG status of 3 or 4, pulmonary infection at the time of SEMS placement, and prior radiation therapy were predictive factors associated with lower overall survival. Dysphagia scores improved significantly 15 days after stent insertion. The overall stent-related adverse event rate was 30%. Stent migration and occlusion caused by tumor overgrowth were the most common adverse events.
SEMS placement is a reasonable treatment option for MERFs; however, ECOG status of 3 or 4 and fistula development during esophageal cancer treatment may be independent predictors of clinical failure after stent placement.
PDF
