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Aim: Cholestasis remains a partially characterized disease. Evidence has been gained that it is a systemic disease that begins in the liver but significantly impacts other organs and systems such as the kidney, heart, and intestine, among others. One of the primary damage mechanisms is the generation of reactive oxygen species (ROS), which eventually leads to oxidative stress, impacting canalicular morphology and actin cytoskeleton changes that could worsen the problem. These characteristics are also observed in the kidney and intestine. The work focused on addressing the intestine effects of intrahepatic cholestasis induced by α-naphthyl isothiocyanate (ANIT) and the protective response of the hepatocyte growth factor (HGF). Methods: The 10- to 12-week-old CD1 male mice were treated with ANIT and then treated or not with HGF; intestine damage was addressed by histology, immunohistochemistry (IHC) of specific markers, oxidative stress, and apoptosis. Results: Results show changes in the intestine histology, particularly the colon and ileum, induced by the cholestasis. HGF treatment restored the histology presentation and reverted the oxidative damage, clearly indicating a healing response. This observation was supported by an increment in anti-inflammatory macrophages (CD163+) in the HGF treatment. Conclusions: The data prove that HGF induces a protective and repairing response in the intestine under cholestatic challenges.

Hepatocellular carcinoma (HCC) is considered one of the most aggressive tumors worldwide. The consumption of lipid-enriched diets, mainly high cholesterol, induces oxidative stress and chronic inflammation, leading to HCC progression. Moreover, fatty acids and cholesterol could display differential responses on immune cells inside the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs) represent one of the most critical leukocytes in the tumor microenvironment (TME) displaying pro-tumoral responses and one of the mainly cholesterol donors to cancer cells. Immunotherapy or cholesterol regulators, alone or combined, would represent an effective strategy for HCC treatment. Nonetheless, steatotic etiology from non-alcoholic fatty liver disease (NAFLD)-HCC tumors has been unexpectedly resulting in highly aggressive behavior.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)–engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) accounts for 85% of primary liver cancer, the third most common cause of cancer-related deaths worldwide. Its incidence has been increasing in both men and women. In Western countries, high-calorie diets, mainly rich in carbohydrates such as fructose, represent a significant concern due to their repercussions on the population’s health. A high-fructose diet is related to the development of Metabolic-Associated Fatty Liver Disease (MAFLD), formerly named Non-Alcoholic Fatty Liver Disease (NAFLD), and the progression of HCC as it potentiates the lipogenic pathway and the accumulation of lipids. However, fructose metabolism seems to be different between the stages of the disease, carrying out a metabolic reprogramming to favor the proliferation, inflammation, and metastatic properties of cancer cells in HCC. This review focuses on a better understanding of fructose metabolism in both scenarios: MAFLD and HCC.

Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment.

Introduction and objective. Non-alcoholic fatty liver disease remains as one of the main liver disorders worldwide. It is widely accepted that is the kind of lipid, rather than the amount deposited in the cells that determines cell damage. Cholesterol and saturated free fatty acids are deleterious lipids when accumulated but, in contrast, there are some valuable lipids that could counteract those with harmful properties. Much of this knowledge arises from studies using a single fatty acid, but the effects of a combination of fatty acids, as obtained by diet has been poorly addressed. In the present work, we were focused to figure out the cellular effect of two different mixes of fatty acids, one with high proportion of saturated fatty acids, and another one with high proportion of unsaturated fatty acids (Mediterranean-like) in a cellular model of steatosis. Material and methods. Primary mouse hepatocytes from animals fed with a western diet (high fat and carbohydrates diet), were treated with both mixes of fatty acids for 24 h. Results. Our data clearly show that only the high unsaturated fatty acid mix induced a decrease in triglycerides (47.5%) and cholesterol (59%) content in steatotic hepatocytes mediating cellular protection associated to the decrement of ROS and oxidative damage. The mixture of high saturated fatty acids exhibited no effects, preserving high levels of cholesterol and triglycerides and oxidative damage. In conclusion, our results show that Mediterranean-like mix of fatty acids exerts cellular protection in steatosis by decreasing triglycerides, cholesterol, ROS content and oxidative damage.

Introduction and Objectives: Hepatocellular carcinoma (HCC) is the most common and aggressive form of liver cancer. Until 2020, worldwide, it has been ranked 5th and 3rd in terms of incidence and mortality, respectively. HCC has various etiologies, but tumors formed by high cholesterol intake induce an aggressive phenotype and high tumor-associated macrophages (TAM) infiltration. TAM acquires an alternative polarity (M2) with immunosuppressive and pro-tumoral activities. HCC patients with high TAM recruitment have a poor prognosis with a low free-survival rate. The design of therapies represents a challenge. The growth differentiation factor 11 (GDF11) has been proposed as a promising molecule for treating HCC, favors a reduction in proliferation, invasion, and lipid metabolism, and therefore reduces the aggressive phenotype. In our research group, we have found that GDF11 also has various effects on cells belonging to the tumor microenvironment, particularly in TAM. Aim: To evaluate TAM polarity and their intercommunication with HCC-derived cells during treatment with GDF11. Materials and Methods: THP-1-macrophages cell line was used; lipopolysaccharides were used for the M1 polarity acquisition and IL-4/13 or conditioned medium (CM) derived from Huh-7 cells for M2 polarity acquisition, flow cytometry (FCM) was used. GDF11 (50 ng/mL) was applied every 24 h up to 3 days. We used anti-Smad2 and 3 antibodies in Western blot (WB). Cell viability and proliferation studies were performed using crystal violet. The quantification of cholesterol was performed using o-Phthaldialdehyde and free radicals’ detection was performed using dihydroethidium. Data were presented as mean ± standard error of the mean (SEM). The analysis of variance (ANOVA) test was used to compare the mean values ​​between groups. Each result has at least 3 independent experiments. Statistical significance was indicated with an asterisk (*P

Introduction and Objectives: HCC is one of the main causes of cancer-related death worldwide and has third place in mortality. One of the main risk factors is metabolic-associated fatty liver disease (MAFLD), having hepatic steatosis, and related metabolic disorders. Mexican population has the highest obesity rate in both children and adults, and the consumption of hypercaloric diets has been related to that. Also, Mexico is in the top five countries with a higher fructose-enriched diet consumption and has been proved already the relation between fructose consumption and MAFLD. Likewise, fructose has been related to metabolic rewiring in transformed cells, enhancing aggressiveness and survival. Aim: To analyze fructose role on aggressiveness promotion of HCC cells. Materials and Methods: We used C57Bl/6J mice strain (both sex) with a high Fructose diet (Fru) (33% of fructose in the drinking water, ad libitum). Fru supplementation started with 15 days-old mice, two days after DEN was injected (10 μg/Kg, i.p), and the treatment was ended 8 months later. The UAM ethics committee approved the protocol. In vitro studies were carried out with the Huh-7 HCC cell line and we evaluated metabolic and biochemical parameters. Results: Tissue samples were analyzed by H&E. We observed that the fructose-enriched diet group mice presented fat accumulation in the hepatocytes and also areas with a greater inflammatory infiltrate (Fru). Mice in the fructose-enriched diet + DEN (Fru/HCC) group showed a marked difference between the tumor area and the surrounding tissue and an increase in the number of bile ducts, indicating liver tissue damage. Also, we analyzed the protein content of some lipogenic enzymes and noticed an increment in fatty acid synthase (Fasn) in Fru and Fru/HCC. Due to that, we analyzed if Fru treatment was inducing metabolic rewiring in transformed cells. We obtained metabolic changes in fructose-treated cells, reducing the glycolytic pathway and the traditional Warburg effect. Then we evaluated if the Huh-7 under a Fru treatment was more dependent on mitochondria or glycolysis ATP generation. We observed a reduction in proliferation under oligomycin treatment vs. 2-DG treatment. At least, we evaluated the pentose phosphate pathway (PPP) under a Fru treatment and obtained a higher glucose-6-phosphate dehydrogenase (G-6-P DH) activity with Fru vs. only glucose (Glc). Also, G-6-P DH had a more efficient activity in the presence of Fru because the time to reach the Vmax is lower vs. Glc. Conclusion: Fructose induces a metabolic rewiring in cancer cells to enhance ATP production, NADPH, and nucleotides to sustain the active lipid synthesis and proliferation. The fructose-enriched diets promote an aberrant lipogenic phenotype enhancing tumor aggressiveness. Conacyt, Froteras de la Ciencia 1320.The authors declare that there is no conflict of interest.

Introduction and objectives: It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. Materials and methods: Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. Results: Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-κB activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. Conclusion: Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a wide-range of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor.

Introduction and objectives: It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. Materials and methods: Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. Results: Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-B activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. Conclusion: Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a widerange of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor. [ABSTRACT FROM AUTHOR]

The growth differentiation factor 11 (GDF11), a member of the superfamily of the transforming growth factor β, has gained relevance in the last few years due to its remarkable effects in cellular biology, particularly in the nervous system, skeletal muscle, the heart, and many epithelial tissues. Some controversies have been raised about this growth factor. Many of them have been related to technical factors but also the nature of the cellular target. In liver biology and pathobiology, the GDF11 has shown to be related in many molecular aspects, with a significant impact on the physiology and the initiation and progression of the natural history of liver diseases. GDF11 has been involved as a critical regulator in lipid homeostasis, which, as it is well known, is the first step in the progression of liver disease. However, also it has been reported that the GDF11 is involved in fibrosis, senescence, and cancer. Although there are some controversies, much of the literature indicates that GDF11 displays effects tending to solve or mitigate pathological states of the liver, with reasonable evidence of correlation with other organs or systems. To a large extent, the controversy, as mentioned, is due to technical problems, such as the specificity of GDF11 antibodies, confusion with its closer family member, myostatin, and the state of differentiation in the tissues. In the present work, we reviewed the specific effects of GDF11 in the biology and pathobiology of the liver as a potential and promising factor for therapeutic intervention shortly. [Display omitted] • GDF11 displays physiological effects on the liver. • GDF11 requires a stemness phenotype for functioning. • GDF11 regulates lipid metabolism. • GDF11 displays anti-tumoral effects. [ABSTRACT FROM AUTHOR]