The gut microbiota has been recognized as an important factor in the development of metabolic diseases such as obesity and is considered an endocrine organ involved in the maintenance of energy homeostasis and host immunity. Dysbiosis can change the functioning of the intestinal barrier and the gut-associated lymphoid tissues (GALT) by allowing the passage of structural components of bacteria, such as lipopolysaccharides (LPS), which activate inflammatory pathways that may contribute to the development of insulin resistance. Furthermore, intestinal dysbiosis can alter the production of gastrointestinal peptides related to satiety, resulting in an increased food intake. In obese people, this dysbiosis seems be related to increases of the phylum Firmicutes, the genus Clostridium, and the species Eubacterium rectale, Clostridium coccoides, Lactobacillus reuteri, Akkermansia muciniphila, Clostridium histolyticum, and Staphylococcus aureus.

Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients.

Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD(+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC.

Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic β cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes.

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A 2 (TXA 2 ) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA 2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA 2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA 2 signaling as a target for the prevention of metastasis.

Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1γ, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1γ release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1γ-bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations.

Objective: To investigate whether a probiotic mix has additional effects when compared with an isolated dietary intervention on the body composition, lipid profile, endotoxemia, inflammation, and antioxidant profile. Methods: Women who had excess weight or obesity were recruited to a randomized, double-blind trial and received a probiotic mix (Lactobacillus acidophilus and casei; Lactococcus lactis; Bifidobacterium bifidum and lactis; 2 3 10 10 colony-forming units/day) (n 5 21) or placebo (n 5 22) for 8 weeks. Both groups received a dietary prescription. Body composition was assessed by anthropometry and dualenergy X-ray absorptiometry. The lipid profile, lipid accumulation product, plasma fatty acids, lipopolysaccharide, interleukin-6, interleukin-10, tumor necrosis factor-a, adiponectin, and the antioxidant enzymes activities were analyzed. Results: In comparison with the dietary intervention group, the dietary intervention 1 probiotic mix group showed a greater reduction in the waist circumference (23.40% vs. 25.48%, P 5 0.03), waist-height ratio (23.27% vs. 25.00%, P 5 0.02), conicity index (22.43% vs. 24.09% P 5 0.03), and plasma polyunsaturated fatty acids (5.65% vs. 218.63%, P 5 0.04) and an increase in the activity of glutathione peroxidase (216.67% vs. 15.62%, P < 0.01). Conclusions: Supplementation of a probiotic mix reduced abdominal adiposity and increased antioxidant enzyme activity in a more effective way than an isolated dietary intervention.

Consumption of tree nuts and legume seeds is associated with a reduction in cardiovascular risk. The reduction in blood lipids and in inflammatory and oxidative processes exhibited by bioactive compounds such as monounsaturated and polyunsaturated fatty acids, fibers, phenolic compounds, tocopherols, phospholipids, carotenoids, some minerals, and arginine, has stimulated research on the mechanisms of action of these substances through distinct experimental approaches. It is, therefore, important to know the metabolic effect of each nut and legume seed or the mixture of them to choose the most suitable nutritional interventions in clinical practice. The aim of this narrative bibliographic review was to investigate the effects of tree nuts and legume seeds on biomarkers of cardiovascular risk, as well as their mechanisms of action with regard to lipid profiles, insulin resistance, arterial pressure, oxidative stress, and inflammation. The findings indicate that a mixture of nuts and legume seeds optimizes the protective effect against cardiovascular risk.