The aim of this study was to assess whether two-years treatment with Pirfenidone influences necroinflammation, fibrosis and steatosis, serum levels of TGF-β1, IL-6, TNF-α and CB1 and CB2 gene ...expression, in patients with chronic hepatitis C (CHC).
Twenty-eight patients out of 34 with CHC virus infection were enrolled in the study and received Pirfenidone (1200 mg/day) for 24 months. Six patients dropped out after 12 months of PFD. Liver biopsies and serum samples were obtained at the beginning and end of treatment. Modified HAI was calculated. CB1 and CB2 gene expression was correlated with fibrosis progression alongside with necroinflammation and steatosis. TGF-β1, IL-6, TNF-α and liver transaminases were measured in serum at two-months intervals. HCV genotype and viral load were also assessed. Quality of life was evaluated by SF36 questionnaires and the prognosis of disease was assessed with Child-Pugh score. The Wilcoxon test matched-pair signed ranks were used to analyze the outcomes.
Intention to treat analyses were performed for biochemistry and clinical parameters. At the end of treatment, necroinflammation grading was reduced in an average of 3.2 points in 82% of patients (p < 0.05) and Ishak's fibrosis stage decreased 2-points average in 67% of patients (p < 0.05). Steatosis decreased in 61% of patients. IL-6 and TGF-β1 serum levels decreased significantly in 93% and 67% of patients (p < 0.05), respectively, while TNF-α diminished in 47% of patients. ALT and AST tended to normalize in 81% of patients; CB2 mRNA levels increased in 86% and CB1 expression diminished in 29% of patients. Both, quality of life and Child-Pugh score improvements were reported in all patients.
Pirfenidone for two years benefits CHC patients and improves inflammation, fibrosis and steatosis in higher number of patients as previously shown for 12-months treatment with PFD. Additionally, PFD improved TGFβ1 and IL-6 levels and diminished liver expression of anti-fibrogenic receptor CB2.
ClinicalTrials.gov identifier: NCT02161952. Protocol Registration Date: 06/11/2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Excess of visceral adipose tissue (VAT) characteristic of obesity leads to a proinflammatory state disrupting the insulin signaling pathway, triggering insulin resistance (IR) and inflammation, the ...main processes contributing to obesity comorbidities. Ursolic acid (UA), a pentacyclic triterpenoid occurring in a variety of plant foods, exhibits anti-inflammatory properties. The aim of this study was to evaluate UA effects on IR, hyperinsulinemia, and inflammation in experimental diet-induced obesity. Forty male Wistar rats were randomly assigned to eight groups (
= 5). One group was used for time 0. Three groups were labeled as OBE (control): receiving high-fat diet (HFD; fat content 45.24% of energy) during 3, 6, or 9 weeks; three groups UA-PREV: exposed to simultaneous HFD and UA during 3, 6, or 9 weeks to evaluate UA preventive effects; one group UA-REV: receiving HFD for 6 weeks, followed by simultaneous HFD and UA for three additional weeks to analyze UA reversal effects. Measurements were performed after 3, 6, or 9 weeks of treatment. Adiposity was calculated by weighing VAT after sacrifice. Serum markers were quantified through colorimetric and enzyme-linked immunosorbent assay methods. VAT adipokines RNAm expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction. Data were analyzed by Kruskal-Wallis and Mann-Whitney
tests. UA significantly decreased adiposity, IR, hyperinsulinemia, triacylglycerides, and cholesterol levels, and also VAT mRNA expression of MCP-1 (monocyte chemoattractant protein-1), IL (interleukin)-1
and IL-6, concomitantly increasing adiponectin levels. UA metabolic effects demonstrated in this study support its potential therapeutic utility to improve IR, hyperinsulinemia, and inflammation observed in obesity and diabetes.
Metabolism-associated fatty liver disease (MAFLD) is the most common liver disease worldwide, and intestinal dysbiosis is associated with its development. Methyl donor supplementation has shown ...beneficial effects for MAFLD treatment; however, its role on the intestinal microbiota and miRNAs hepatic expression has been poorly studied. The aim of this study was to evaluate the effect of methyl group donor supplementation on gut microbiota and hepatic expression of key miRNAs in a murine model of MAFLD.
Twenty-four male C57BL/6J mice were divided into three groups: 1) Control: Conventional diet. 2) HF/FS: Diet rich in fats and sugars for 18 weeks. 3) HFMS: HF/FS diet for the first 10 weeks, followed by a HF/FS diet plus orogastric supplementation with methyl group donors for the last 8 weeks.
The intestinal microbiota was characterized by 16S rRNA gene sequencing; supplementation with methyl donors modified microbial composition analyzed by beta diversity. In addition, HFMS group strongly tended to increase alpha diversity and induced enrichment of six genus: Acinetobacter, Anaeroplasma, Pseudomonas, Stenotrophomonas, Tuzzerella, and Moraxellaceae family. HFMS group significantly increased SCFAs fecal concentration and restored intestinal permeability dysfunction by increasing Ocln and Cldn1 expression; consequently, a decrease in liver inflammation was observed due to a decrease in Tnf-a expression. On the other hand, HFMS group significantly increased hepatic expression of miR-122 and decreased miR-33a expression.
This study offers valuable insights into the role of methyl donors as microbiota modifiers, highlighting their ability to promote restoration of intestinal health and liver metabolism. These findings contribute to the proposition that methyl donors could be a promising strategy for treating MAFLD and hepatic related conditions.
The microbial communities’ control is crucial to maintaining homeostasis of gut-liver axis; clinical evidence demonstrates disruptions of microbiota-gut-liver in individuals with Metabolic-associated ...fatty liver disease (MAFLD). Foods rich in fiber and polyphenols have been associated with an improvement in microbiota diversity, indexand miRNAs expression. The aim of this study was to evaluate the effect of a supplementation with a mixture of Mexican foods (MexMix): Opuntia ficus indica (nopal), Theobroma cacao (cocoa) and Acheta domesticus (crickets) on gut-liver axis in a MAFLD mice model.
Thirty C57BL/6J mice were divided into three groups: 1) control: normal diet. 2) HF: high fat diet (60%) and fructose/sucrose water 3) MexMix: HF diet up to week 10, followed by HF diet supplemented with 6.7% nopal, 8.7% cocoa, and 8.7% cricket for 8 weeks.
The MexMix animals showed a significantly decreased in body weight, visceral and epididymal fat, adipocyte size, triglycerides, insulin, leptin, and PAI-1; while adiponectin levels increased. Using 16S rRNA gene sequencing, MexMix increased phylogenetic diversity, Firmicutes abundance, and enrichment of 10 beneficial genera, including Lachnospiraceae, Ruminococcaceae, Akkermansia, and Eubacterium_coprostanoligenes_group. In the gut, MexMix supplementation significantly increased SCFAs concentration, intestinal crypts depth, Ocln and Cldn1 expression, and decreased Il6 and Tnf-a expression. In liver, MexMix significantly reduced steatosis and Tnfa expression. Besides, MexMix increased nuclear translocation of NFR2 and, in consequence, a higher hepatic expression of Cat and Sod. MexMix also decreased hepatic expression of miRNA-34a, miRNA-103, and miRNA-33a.
Synchronous supplementation with three nutraceuticals, nopal, cacao, and cricket, produced better results compared to previous studies where foods were administered individually. MexMix demonstrated its efficacy as a prebiotic, promoting the growth of beneficial genera and improving intestinal health. These findings indicate that MexMix has the potential to serve as a therapeutic approach for treating MAFLD in patients, as well as other conditions associated with excessive consumption of fats and sugars.
Obesity is an epidemic in the world, linked with insulin resistance, nonalcoholic steatohepatitis (NASH), and cardiovascular diseases (CVDs), being the latter main cause of global death. NASH ...progresses with inflammation with or without hepatic fibrosis, including a hormonal dysregulation. Pirfenidone (PFD) have anti-inflammatory and anti-fibrotic effects. However, its effects on hormonal regulation are completely unknown. The aim of this study was to investigate the effects of PFD on hormonal expression levels, related to the lipids and carbohydrates metabolism in high-fat/high-carbohydrate (HFHC)-diet-induced obese male C57BL/6J mice.
Twenty-week-old mice were fed with normal diet (ND, 3.1 kcal/g, n=7) and HFHC (65.1 kcal/g, water with 2.31% fructose and 1.89% sucrose, n=14) diet for 16 weeks; at 8 weeks, seven mice with HFHC were administered PFD (300 mg/kg/day) by gavage. ITT, ELISA, dry-chemistry, ELISA, histologies and SPSS were analyzed.
HFHC mice development NASH and myocarditis with fibrosis in both tissues (P≤0.05). HFHC showed elevated resistin and aspartate aminotransferase (P≤0.05). Parameters significantly increased in HFHC (P≤0.05), were ameliorated by PFD, such as weight (body, liver, and heart), tibia length, epididymal fat, hepatic steatosis, hormones (insulin, glucagon, leptin, plasminogen activator inhibitor 1), lipid profile (total cholesterol, triglycerides, LDL, and VLDL), as well as inflammatory foci and fibrosis in hepatic and cardiac tissue (P≤0.05). Moreover, PFD reduced alanine aminotransferase (P≤0.05).
In the current work, we showed that PFD increases hormone expression levels, which are implicated in the lipids and carbohydrates metabolism, and also improves expression levels of lipid profile and lipoproteins related with NASH and CVDs. These findings contribute and support the potential therapeutic of PFD for the prevention of NASH and cardiovascular disease development induced by obesity.
: Metabolic alterations and alcohol consumption are the most common etiological agents related to hepatic steatosis (HS) development. There is little evidence that shows the effects generated by ...synergy of both etiologic agents. N-acetyl cysteine (NAC) is a drug whose efficacy in the early stages of SH, generated by a hypercaloric diet plus alcohol consumption, is unknown.
The aim of this work was to evaluate NAC effects on oxidative stress, and metabolic alterations induced in HS experimentally induced by chronic ethanol consumption plus a hypercaloric diet.
C57BL/6J mice (n=4) grouped into 1) Control; 2) HF/OH, administrated with hypercaloric diet and ethanol; 3) HF/OH+NAC, same treatments of group 2 plus NAC. Serum markers of liver damage and anorexigenic and orexigenic adipokines were evaluated; oxidative stress markers in liver samples were analyzed; finally, a H&E stain was performed. This project was conducted in accordance with the guidelines of the University of Guadalajara under the approval number of the bioethics, research, and ethics research committees CI-02920.
NAC prevents weight gain and metabolic alterations generated by concomitant consumption of a hypercaloric diet and alcohol; this drug improves changes in anorexigenic and orexigenic adipokines such as leptin, ghrelin, resistin, GLP-1, and modulates total, HDL, and LDL cholesterol levels. On the other hand, NAC reduces CYP2E1 and alcohol dehydrogenase expression, as well as the oxidative environment induced by both etiological agents, by avoiding an increase in malondialdehyde levels, promoting Nrf2 transcription factor expression and superoxide dismutase; also preventing an increase in the expression of Catalase. Finally, H&E staining showed that NAC prevents the development of tissue alterations in the liver parenchyma generated by the consumption of a hypocaloric diet plus alcohol.
In this work, we demonstrate that NAC prevents metabolic alterations and oxidative damage related to early phases of HS induced by concomitant consumption of alcohol plus a hypercaloric diet. These effects would slow down the development of more severe stages of this disease.
We report the use of transition metal nanoparticles (Ni or Co) to longitudinally cut open multiwalled carbon nanotubes in order to create graphitic nanoribbons. The process consists of catalytic ...hydrogenation of carbon, in which the metal particles cut sp2 hybridized carbon atoms along nanotubes that results in the liberation of hydrocarbon species. Observations reveal the presence of unzipped nanotubes that were cut by the nanoparticles. We also report the presence of partially open carbon nanotubes, which have been predicted to have novel magnetoresistance properties.1 The nanoribbons produced are typically 15−40 nm wide and 100−500 nm long. This method offers an alternative approach for making graphene nanoribbons, compared to the chemical methods reported recently in the literature.
Abstract
miRNAs are involved in the development of metabolic associated fatty liver disease (MAFLD) and nonalcoholic steatohepatitis (NASH). We aimed to evaluate modifications by prolonged-release ...pirfenidone (PR-PFD) on key hepatic miRNAs expression in a MAFLD/NASH model. First, male C57BL/6J mice were randomly assigned into groups and fed with conventional diet (CVD) or high fat and carbohydrate diet (HFD) for 16 weeks. At the end of the eighth week, HFD mice were divided in two and only one half was treated with 300 mg/kg/day of PR-PFD mixed with food. Hepatic expression of miRNAs and target genes that participate in inflammation and lipid metabolism was determined by qRT-PCR and transcriptome by microarrays. Increased hepatic expression of miR-21a-5p, miR-34a-5p, miR-122-5p and miR-103-3p in MAFLD/NASH animals was reduced with PR-PFD. Transcriptome analysis showed that 52 genes involved in lipid and collagen biosynthesis and inflammatory response were downregulated in PR-PFD group. The expression of
Il1b
,
Tnfa
,
Il6
,
Tgfb1
,
Col1a1
, and
Srebf1
were decreased in PR-PFD treated animals. MAFLD/NASH animals compared to CVD group showed modifications in gene metabolic pathways implicated in lipid metabolic process, inflammatory response and insulin resistance; PR-PFD reversed these modifications.
Monkeypox is the most prevalent Orthopoxvirus zoonosis infection since the eradication of smallpox. The current multi-country outbreak involves five WHO regions affecting mainly Europe. Accurate ...clinical and virological aspects of the disease outside endemic areas are needed.
We performed an observational study of cases diagnosed in Madrid (Spain) (May/June 2022). Confirmation from vesicular lesions swabs, Orthopoxvirus real-time PCR, sequencing, phylogenetic analysis, and direct detection by Electron microscopy was performed. In addition, a structured epidemiological questionnaire was completed systematically to gather sociodemographic, clinical, and behavioral data from all confirmed cases.
We extracted data from 48 patients, all cisgender men. The median age was 35 years (IQR 29 - 44), and 87.5% were MSM. The most prevalent symptoms were the presence of vesicular-umbilicated and pseudo-pustular skin lesions (93.8%), asthenia (66.6%), and fever (52.1%). In addition, the location of the lesions in the genital or perianal area was related to the role in sexual intercourse (p<0.001). Sequencing analysis indicated the virus circulating in Spain belongs to the western African clade. Like the other European cases in the outbreak, the Spanish isolates are a direct descendant of viruses previously detected in Nigeria, the UK, Singapore, and Israel in 2017-2018.
Monkeypox is an emerging infectious disease in Europe where community transmission is reported, mainly in MSM. The first symptom was skin lesions instead of classical fever and rash. The disease follows a self-limited course, and there have been no cases with a serious presentation or severe complications.
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