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Obesity is nowadays considered a pandemic which prevalence's has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules (adipokines, cytokines, hormones), responsible for altering the metabolic, inflammatory, and immune landscape. The crosstalk between adipocytes and tumor cells fuels the tumor microenvironment with pro-inflammatory factors, promoting tissue injury, mutagenesis, invasion, and metastasis. Although classically established as a risk factor for cancer and treatment toxicity, recent evidence suggests mild obesity is related to better outcomes, with obese cancer patients showing better responses to treatment when compared to lean cancer patients. This phenomenon is termed obesity paradox and has been reported in different types and stages of cancer. The mechanisms underlying this paradoxical relationship between obesity and cancer are still not fully described but point to systemic alterations in metabolic fitness and modulation of the tumor microenvironment by obesity-associated molecules. Obesity impacts the response to cancer treatments, such as chemotherapy and immunotherapy, and has been reported as having a positive association with immune checkpoint therapy. In this review, we discuss obesity's association to inflammation and cancer, also highlighting potential physiological and biological mechanisms underlying this association, hoping to clarify the existence and impact of obesity paradox in cancer development and treatment.

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This study aimed to evaluate the effect of a single administration of IB-MECA, an A3 adenosine receptor agonist, upon the nociceptive response and central biomarkers of rats submitted to chronic pain models. A total of 136 adult male Wistar rats were divided into two protocols: (1) chronic inflammatory pain (CIP) using complete Freund's adjuvant and (2) neuropathic pain (NP) by chronic constriction injury of the sciatic nerve. Thermal and mechanical hyperalgesia was measured using von Frey (VF), Randal-Selitto (RS), and hot plate (HP) tests. Rats were treated with a single dose of IB-MECA (0.5 µmol/kg i.p.), a vehicle (dimethyl sulfoxide-DMSO), or positive control (morphine, 5 mg/kg i.p.). Interleukin 1ß (IL-1ß), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels were measured in the brainstem and spinal cord using enzyme-linked immunosorbent assay (ELISA). The establishment of the chronic pain (CIP or NP) model was observed 14 days after induction by a decreased nociceptive threshold in all three tests (GEE, P < 0.05). The antinociceptive effect of a single dose of IB-MECA was observed in both chronic pain models, but this was more effective in NP model. There was an increase in IL-1ß levels promoted by CIP. NP model promoted increase in the brainstem BDNF levels, which was reversed by IB-MECA.

Assuntos

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Neuromodulatory techniques have been studied to treat drug addiction or compulsive eating as well as different chronic pain conditions, such as neuropathic and inflammatory pain in the clinical and preclinical settings. In this study, we aimed to investigate the effect of transcranial direct current stimulation (tDCS) on the association of alcohol withdrawal with neuropathic pain based on nociceptive and neurochemical parameters in rats. Thirty-six adult male Wistar rats were randomized into five groups: control, neuropathic pain, neuropathic pain + tDCS, neuropathic pain + alcohol, and neuropathic pain + alcohol + tDCS. The neuropathic pain model was induced by chronic constriction injury (CCI) to the sciatic nerve. Rats were then exposed to alcohol (20%) by oral gavage administration for 15 days (beginning 24 h after CCI). tDCS was started on the 17th day after surgery and lasted for 8 consecutive days. The nociceptive test (hot plate) was performed at baseline, 16 days after CCI, and immediately and 24 h after the last session of tDCS. Rats were killed by decapitation, and structures were removed and frozen for biochemical analysis (nerve growth factor and interleukin (IL-1α, IL-1ß, and IL-10 measurements). Neuropathy-induced thermal hyperalgesia was reversed by tDCS, an effect that was delayed by alcohol abstinence. In addition, tDCS treatment induced modulation of central levels of IL-1α, IL-1ß, and IL-10 and neurotrophic growth factor. We cannot rule out that the antinociceptive effect of tDCS could be related to increased central levels of IL-1α and IL-10. Therefore, tDCS may be a promising non-pharmacological therapeutic approach for chronic pain treatment.

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Omega 3-docosahexaenoic acid (DHA) and vitamin E Delta-tocotrienol (Delta-T3) are extensively studied as protective nutrients against cancer development. Little is known about the biological mechanisms targeted by these bioactive molecules on lipid droplet (LD) biogenesis, an important breast cancer aggressiveness marker, and the occurrence of lipophagy in breast cancer cells. The aim of this study was to investigate the effect of DHA, Delta-T3 and DHA plus Delta-T3 co-treatment in LD biogenesis and lipophagy process in triple negative breast cancer cell line MDA-MB-231. Cells were treated with 50 µM DHA and/or 5 µM Delta-T3. Our results demonstrated that DHA can trigger an increase in LD biogenesis and co-treatment with Delta-T3 was able to reduce this LD biogenesis. In addition, we showed that a higher cytoplasmic LD content is associated with a higher breast cancer cells malignance and proliferation. Reduction of cytoplasmic LD content by silencing ADRP (adipose differentiation-related protein), a structural LD protein, also decreased cell proliferation in MDA-MB-231 cells. Treatment with DHA and Delta-T3 alone or co-treatment did not reduce cell viability. Moreover, we showed here that DHA can trigger lipophagy in MDA-MB-231 cells and DHA plus Delta-T3 co-treatment was able to enhance this lipophagy process. Our findings demonstrated that co-treatment with DHA plus Delta-T3 in MDA-MB-231 cells could reduce LD biogenesis and potentiate lipophagy in these cells, possibly having a positive impact to inhibit breast cancer malignancy. Therefore, suitable doses of DHA and Delta-T3 vitamin E isoform supplementation can be a prominent tool in therapeutic treatments against breast cancer.

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A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

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The implication of inflammation in pathophysiology of several type of cancers has been under intense investigation. Omega-3 fatty acids can modulate inflammation and present anticancer effects, promoting cancer cell death. Pyroptosis is an inflammation related cell death and so far, the function of docosahexaenoic acid (DHA) in pyroptosis cell death has not been described. This study investigated the role of DHA in triggering pyroptosis activation in breast cancer cells. MDA-MB-231 breast cancer cells were supplemented with DHA and inflammation cell death was analyzed. DHA-treated breast cancer cells triggered increased caspase-1and gasdermin D activation, enhanced IL-1ß secretion, translocated HMGB1 towards the cytoplasm, and membrane pore formation when compared to untreated cells, suggesting DHA induces pyroptosis programmed cell death in breast cancer cells. Moreover, caspase-1 inhibitor (YVAD) could protect breast cancer cells from DHA-induced pyroptotic cell death. In addition, membrane pore formation showed to be a lysosomal damage and ROS formation-depended event in breast cancer cells. DHA triggered pyroptosis cell death in MDA-MB-231by activating several pyroptosis markers in these cells. This is the first study that shows the effect of DHA triggering pyroptosis programmed cell death in breast cancer cells and it could improve the understanding of the omega-3 supplementation during breast cancer treatment.

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[This corrects the article DOI: 10.1186/s12935-017-0451-5.].

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BACKGROUND: In cancer cells, autophagy can act as both tumor suppressor, when autophagic event eliminates cellular contends which exceeds the cellular capacity of regenerate promoting cell death, and as a pro-survival agent removing defective organelles and proteins and helping well-established tumors to maintain an accelerated metabolic state while still dealing with harsh conditions, such as inflammation. Many pathways can coordinate the autophagic process and one of them involves the transcription factors called PPARs, which also regulate cellular differentiation, proliferation and survival. The PPARγ activation and autophagy initiation seems to be interrelated in a variety of cell types. METHODS: Caco-2 cells were submitted to treatment with autophagy and PPARγ modulators and the relationship between both pathways was determined by western blotting and confocal microscopy. The effects of such modulations on Caco-2 cells, such as lipid bodies biogenesis, cell death, proliferation, cell cycle, ROS production and cancer stem cells profiling were analyzed by flow cytometry. RESULTS: PPARγ and autophagy pathways seem to be overlap in Caco-2 cells, modulating each other in different ways and determining the lipid bodies biogenesis. In general, inhibition of autophagy by 3-MA leaded to reduced cell proliferation, cell cycle arrest and, ultimately, cell death by apoptosis. In agreement with these results, ROS production was increased in 3-MA treated cells. Autophagy also seems to play an important role in cancer stem cells profiling. Rapamycin and 3-MA induced epithelial and mesenchymal phenotypes, respectively. CONCLUSIONS: This study helps to elucidate in which way the induction or inhibition of these pathways regulate each other and affect cellular properties, such as ROS production, lipid bodies biogenesis and cell survive. We also consolidate autophagy as a key factor for colorectal cancer cells survival in vitro, pointing out a potential side effect of autophagic inhibition as a therapeutic application for this disease and demonstrate a novel regulation of PPARγ expression by inhibition of PI3K III.