Effects of Foods of Mesoamerican Origin in Adipose Tissue and Liver-Related Metabolism.

Adipose tissue and liver metabolism play a key role in maintaining body homeostasis; therefore, their impairment conduces a pathological state. Nowadays, occidental lifestyle is a common etiological issue among a variety of chronic diseases, while diet is a unique strategy to prevent obesity and liver metabolism impairment and is a powerful player in the treatment of metabolic-related diseases. Mesoamerican foods are rich in bioactive molecules that enhance and improve adipose tissue and liver performance and represent a prophylactic and therapeutic alternative for disorders related to the loss of homeostasis in the metabolism of these two important tissues.

Breastfeeding-Related Health Benefits in Children and Mothers: Vital Organs Perspective.

Breast milk (BM) is a constantly changing fluid that represents the primary source of nutrition for newborns. It is widely recognized that breastfeeding provides benefits for both the child and the mother, including a lower risk of ovarian and breast cancer, type 2 diabetes mellitus, decreased blood pressure, and more. In infants, breastfeeding has been correlated with a lower risk of infectious diseases, obesity, lower blood pressure, and decreased incidence of respiratory infections, diabetes, and asthma. Various factors, such as the baby's sex, the health status of the mother and child, the mother's diet, and the mode of delivery, can affect the composition of breast milk. This review focuses on the biological impact of the nutrients in BM on the development and functionality of vital organs to promote the benefit of health.

Dietary supplementation with Mexican foods, Opuntia ficus indica, Theobroma cacao, and Acheta domesticus: Improving obesogenic and microbiota features in obese mice.

Introduction: An obesogenic diet, a diet high in saturated fats and sugars, is a risk factor for the development of multiple obesity-related diseases. In this study, our aim was to evaluate the effect of supplementation with a mixture of Mexican functional foods (MexMix), Opuntia ficus indica (nopal), Theobroma cacao, and Acheta domesticus (edible crickets), compared with a high-fat and fructose/sucrose diet on an obesogenic mice model. Methods: For this study, 18 male C57BL/6J mice were used, which were divided into three groups: (1) control group: normal diet (ND), (2) HF/FS group: high-fat diet along with 4.2% fructose/sucrose and water (ad libitum access), and (3) therapeutic group (MexMix): HF/FS diet up to week 8, followed by HF/FS diet supplemented with 10% nopal, 10% cocoa, and 10% cricket for 8 weeks. Results: MexMix mice showed significantly reduced body weight, liver weight, visceral fat, and epididymal fat compared with HF/FS mice. Levels of triglycerides, cholesterol, LDL cholesterol, insulin, glucose, GIP, leptin, PAI-1, and resistin were also significantly reduced. For identifying the gut microbiota in the model, 16S rRNA gene sequencing analysis was performed, and the results showed that MexMix supplementation increased the abundance of Lachnospira, Eubacterium coprostanoligenes, and Blautia, bacteria involved in multiple beneficial metabolic effects. It is noteworthy that the mice supplemented with MexMix showed improvements in cognitive parameters, as evaluated by the novel object recognition test. Conclusion: Hence, supplementation with MexMix food might represent a potential strategy for the treatment of obesity and other diseases associated with excessive intake of fats and sugars.

PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases.

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs' critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge.

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

Gene therapy with urokinase-type plasminogen activator regenerates liver tissue.

BACKGROUND AND OBJECTIVES: Gene therapy using urokinase-type plasminogen activator (uPA) has been shown to induce extracellular matrix degradation, hepatocyte proliferation and liver tissue function restoration in liver cirrhosis models. Physiologically, uPA activates plasminogen conversion to plasmin, which leads, depending on the organ, to thrombolysis or extracellular matrix degradation. The purpose of this study was to compare the regenerative effect of gene therapy with adenoviruses encoding wild-type uPA (huPA), as well as its truncated isoform (ΔhuPA), in healthy and cirrhotic animals. In addition, possible adverse effects on coagulation were assessed. METHODS: 6 x 1011 vp/kg of Ad-huPA or Ad-ΔhuPA were administered via the iliac vein to healthy male Wistar rats or to male Wistar rats with cirrhosis induced by chronic poisoning with carbon tetrachloride (CCl4). The animals were sacrificed at day 2, 4 or 6 post-treatment. Liver fibrosis, proliferating cell nuclear antigen expression, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels and coagulation markers were evaluated. RESULTS: On day 6 post-treatment, a fibrosis reversal of 48.7-41.5% was achieved. AST and ALT levels did not change in cirrhotic animals treated with ΔhuPA, but showed an elevation in healthy animals. Cell proliferation increased in healthy and cirrhotic animals with both transgene isoforms. No coagulation adverse effects were observed in the ΔhuPA group, and by day 6, they had disappeared in the huPA group. CONCLUSIONS: Gene therapy with Ad-huPA and Ad-ΔhuPA favors cell proliferation in cirrhotic animals, without important side effects.

ANTECEDENTES Y OBJETIVOS: La terapia génica empleando el activador de plasminógeno tipo urocinasa (huPA) ha demostrado que induce la degradación de matriz extracelular, la proliferación de hepatocitos y el restablecimiento de la funcionalidad tisular en modelos de cirrosis hepática. Fisiológicamente, el uPA activa la conversión del plasminógeno en plasmina, lo que conlleva, dependiendo del órgano, una trombólisis o a degradación de la matriz extracelular. El objetivo de este estudio fue comparar el efecto regenerador de la terapia génica con adenovirus codificando la forma silvestre (huPA), así como su isoforma truncada (DhuPA) en animales sanos y cirróticos. Además, se valoraron los posibles efectos adversos sobre la coagulación. MÉTODOS: Se administró 6x1011 pv/kg del Ad-huPA o Ad-ΔhuPA a ratas Wistar macho sanas o con cirrosis por intoxicación crónica con tetracloruro de carbono (CCl4) vía vena ilíaca. El sacrificio fue al día 2, 4 o 6 postratamiento. Se evaluó la fibrosis hepática, la expresión de antígeno nuclear de proliferación celular y niveles séricos de alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST), y marcadores de coagulación. RESULTADOS: Al día 6 postratamiento se alcanzó una reversión de fibrosis del 48.7-41.5%. Los niveles de AST y ALT no cambiaron en animales cirróticos tratados con DhuPA, pero aumentaron en animales sanos comparados con el control sano no tratado. La proliferación aumenta en animales sanos y cirróticos con ambas isoformas del transgén. No se observaron efectos adversos en la coagulación en el grupo DhuPA y para el día 6 habían desaparecido en el grupo huPA. CONCLUSIONES: La terapia génica con Ad-uPA y Ad-ΔhuPA favorece la proliferación celular en animales cirróticos, sin efectos secundarios importantes.

Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury.

Adenoviral vector AdhMMP8 (human Metalloproteinase-8 cDNA) administration has been proven beneficial in various experimental models of liver injury improving liver function and decreasing fibrosis. In this study, we evaluated the potential therapeutic AdhMMP8 effect in a chronic kidney damage experimental model. Chronic injury was induced by orogastric adenine administration (100mg/kg/day) to Wistar rats for 4 weeks. AdhMMP8 (3x1011vp/kg) was administrated in renal vein during an induced-ligation-ischemic period to facilitate kidney transduction causing no-additional kidney injury as determined by histology and serum creatinine. Animals were sacrificed at 7- and 14-days post-Ad injection. Fibrosis, histopathological features, serum creatinine (sCr), BUN, and renal mRNA expression of αSMA, Col-1α, TGF-ß1, CTGF, BMP7, IL-1, TNFα, VEGF and PAX2 were analyzed. Interestingly, AdhMMP8 administration resulted in cognate human MMP8 protein detection in both kidneys, whereas hMMP8 mRNA was detected only in the left kidney. AdhMMP8 significantly reduced kidney tubule-interstitial fibrosis and glomerulosclerosis. Also, tubular atrophy and interstitial inflammation were clearly decreased rendering improved histopathology, and down regulation of profibrogenic genes expression. Functionally, sCr and BUN were positively modified. The results showed that AdhMMP8 decreased renal fibrosis, suggesting that MMP8 could be a possible therapeutic candidate for kidney fibrosis treatment.

Therapies Based on Nanoparticles for Eye Drug Delivery.

Eye drug delivery, particularly to the retina, is a technical hurdle that needs to be solved and represents an ongoing current important medical field. Posterior segment eye diseases are a major cause of visual impairment worldwide. Age-related macular degeneration, glaucoma, and diabetic retinopathy are the major causes of blindness. To achieve efficient drug delivery and drug retention time in the posterior segment of the eye, novel delivery systems based on nanoparticles have been developed in the last few years. Nowadays, liposomes represent the most utilized nanoparticles for eye drug delivery and, recently, a broad spectrum of diverse nanoparticles continue to emerge with special characteristics representing ideal candidates for eye drug delivery.

Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK.

Nonalcoholic steatohepatitis (NASH) is recognized by hepatic lipid accumulation, inflammation, and fibrosis. No studies have evaluated the prolonged-release pirfenidone (PR-PFD) properties on NASH features. The aim of this study is to evaluate how PR-PFD performs on metabolic functions, and provide insight on a mouse model of human NASH. Male C57BL/6J mice were fed with either normo diet or high-fat/carbohydrate diet for 16 weeks and a subgroup also fed with PR-PFD (300 mg/kg/day). An insulin tolerance test was performed at the end of treatment. Histological analysis, determination of serum hormones, adipocytokines measurement, and evaluation of proteins by western blot was performed. Molecular docking, in silico site-directed mutagenesis, and in vitro experiments using HepG2 cultured cells were performed to validate PR-PFD binding to peroxisome proliferator-activated receptor alpha (PPAR-α), activation of PPAR-α promoter, and sirtuin 1 (SIRT1) protein expression. Compared with the high-fat group, the PR-PFD-treated mice displayed less weight gain, cholesterol, very low density lipoprotein and triglycerides, and showed a significant reduction of hepatic macrosteatosis, inflammation, hepatocyte ballooning, fibrosis, epididymal fat, and total adiposity. PR-PFD restored levels of insulin, glucagon, adiponectin, and resistin along with improved insulin resistance. Noteworthy, SIRT1-liver kinase B1-phospho-5' adenosine monophosphate-activated protein kinase signaling and the PPAR-α/carnitine O-palmitoyltransferase 1/acyl-CoA oxidase 1 pathway were clearly induced in high fat + PR-PFD mice. In HepG2 cells incubated with palmitate, PR-PFD induced activation and nuclear translocation of both PPARα and SIRT1, which correlated with increased SIRT1 phosphorylated in serine 47, suggesting a positive feedback loop between the two proteins. These results were confirmed with both synthetic PPAR-α and SIRT1 activators and inhibitors. Finally, we found that PR-PFD is a true agonist/ligand for PPAR-α. Conclusions: PR-PFD provided an anti-steatogenic effect and protection for inflammation and fibrosis.

Hydrodynamics-based liver transfection achieves gene silencing of CB1 using short hairpin RNA plasmid in cirrhotic rats.

BACKGROUND: There is a correlation between the endocannabinoid system and hepatic fibrosis based on the activation of CB1 and CB2 receptors; where CB1 has profibrogenic effects. Gene therapy with a plasmid carrying a shRNA for CB1 delivered by hydrodynamic injection has the advantage of hepatic tropism, avoiding possible undesirable effects of CB1 pharmacological inhibition. OBJECTIVE: To evaluate hydrodynamics-based liver transfection in an experimental model of liver cirrhosis of a plasmid with the sequence of a shRNA for CB1 and its antifibrogenic effects. METHODS: Three shRNA (21pb) were designed for blocking CB1 mRNA at positions 877, 1232 and 1501 (pshCB1-A, B, C). Sequences were cloned in the pENTR™/U6. Safety was evaluated monitoring CB1 expression in brain tissue. The silencing effect was determined in rat HSC primary culture and CCl4 cirrhosis model. Hydrodynamic injection in cirrhotic liver was through iliac vein and with a dose of 3mg/kg plasmid. Serum levels of liver enzymes, mRNA levels of TGF-ß1, Col IA1 and α-SMA and the percentage of fibrotic tissue were analyzed. RESULTS: Hydrodynamic injection allows efficient CB1 silencing in cirrhotic livers and pshCB1-B (position 1232) demonstrated the main CB1-silencing. Using this plasmid, mRNA level of fibrogenic molecules and fibrotic tissue considerably decrease in cirrhotic animals. Brain expression of CB1 remained unaltered. CONCLUSION: Hydrodynamics allows a hepatotropic and secure transfection in cirrhotic animals. The sequence of the shCB1-B carried in a plasmid or any other vector has the potential to be used as therapeutic strategy for liver fibrosis.

Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis.

BACKGROUND AND AIMS: hADSCs transplantation in cirrhosis models improves liver function and reduces fibrosis. In addition, Ad-huPA gene therapy diminished fibrosis and increased hepatocyte regeneration. In this study, we evaluate the combination of these therapies in an advanced liver fibrosis experimental model. METHODS: hADSCs were expanded and characterized before transplantation. Ad-huPA was simultaneously administrated via the ileac vein. Animals were immunosuppressed by CsA 24 h before treatment and until sacrifice at 10 days post-treatment. huPA liver expression and hADSCs biodistribution were evaluated, as well as the percentage of fibrotic tissue, hepatic mRNA levels of Col-αI, TGF-ß1, CTGF, α-SMA, PAI-I, MMP2 and serum levels of ALT, AST and albumin. RESULTS: hADSCs homed mainly in liver, whereas huPA expression was similar in Ad-huPA and hADSCs/Ad-huPA groups. hADSCs, Ad-huPA and hADSCs/Ad-huPA treatment improves albumin levels, reduces liver fibrosis and diminishes Collagen α1, CTGF and α-SMA mRNA liver levels. ALT and AST serum levels showed a significant decrease exclusively in the hADSCs group. CONCLUSIONS: These results showed that combinatorial effect of cell and gene-therapy does not improve the antifibrogenic effects of individual treatments, whereas hADSCs transplantation seems to reduce liver fibrosis in a greater proportion.

Myeloperoxidase enzymatic activity is increased in patients with different levels of dental crowding after initial orthodontic activation.

INTRODUCTION: Orthodontic tooth movement implies application of forces that generate an inflammatory process. The myeloperoxidase (MPO) enzyme is found inside neutrophil granules. MPO activity indirectly reflects the level of inflammation. The aim of this study was to measure MPO activity in gingival crevicular fluid (GCF) and whole saliva in orthodontic patients with different levels of dental crowding at the alignment phase of orthodontic treatment with the same archwires. METHODS: Twenty patients were classified according to the irregularity index into 2 groups: severe and minimum crowding (10 in each group). MPO activity was evaluated in GCF and saliva at 0 and 2 hours, and 7 and 14 days after the orthodontic appliances were activated. MPO activity was measured using the modified Bradley-Bozeman technique. RESULTS: In both groups, the maximum activity was at 2 hours (P <0.05) after activation. MPO activity remained elevated until day 7, and values similar to baseline were found at day 14 in the GCF and saliva samples. Enzymatic activity did not show statistical differences between the groups. CONCLUSIONS: The amount of dental crowding does not seem to influence MPO activity, which showed similar patterns in GCF and saliva, but the values in GCF reflected the inflammatory changes more accurately than did the values in saliva. The quantification of MPO activity is a useful biologic marker as an indirect measurement of inflammation generated with tooth movement independent of the amount of crowding.