Spectroscopic data often contain artifacts or noise related to the sample characteristics, instrumental variations, or experimental design flaws. Therefore, classifying the raw data is not recommended and might lead to biased results. Nevertheless, most issues may be addressed through appropriate data pre-processing. Effective pre-processing is particularly crucial in critical applications like liquid biopsy for disease detection, where even minor performance improvements may impact patient outcomes. Unfortunately, there is no consensus regarding optimal pre-processing, complicating cross-study comparisons. This study presents a comprehensive evaluation of various pre-processing methods and their combinations to assess their influence on classification results. The goal was to identify whether some pre-processing methods are associated with higher classification outcomes and find an optimal strategy for the given data. Data from Raman optical activity and infrared and Raman spectroscopy were processed, applying tens of thousands of possible pre-processing pipelines. The resulting data were classified using three algorithms to distinguish between subjects with liver cirrhosis and those who had developed hepatocellular carcinoma. Results highlighted that some specific pre-processing methods often ranked among the best classification results, such as the Rolling Ball for correcting the baseline of Raman spectra or the Doubly Reweighted Penalized Least Squares and Mixture model in the case of Raman optical activity. On the other hand, the selection of filtering and/or normalization approach usually did not have a significant impact. Nonetheless, the pre-processing of top-scoring pipelines also depended on the classifier utilized. The best pipelines yielded an AUROC of 0.775-0.823, varying with the evaluated spectroscopic data and classifier.

• Klíčová slova
• Chiroptical spectroscopy, Classification, Data pre-processing, Diagnostics, Liquid biopsy, Machine learning, Vibrational spectroscopy,
• MeSH
• algoritmy MeSH
• hepatocelulární karcinom * diagnóza   patologie   MeSH
• jaterní cirhóza diagnóza   patologie   MeSH
• lidé MeSH
• metoda nejmenších čtverců MeSH
• nádory jater * diagnóza   patologie   MeSH
• Ramanova spektroskopie * metody   MeSH
• spektrofotometrie infračervená metody   MeSH
• tekutá biopsie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder that can progress to metabolic dysfunction-associated steatohepatitis (MASH), potentially leading to liver fibrosis, cirrhosis, and cancer. As there is no sufficient specific pharmacological treatment for the progression of MASLD to MASH, we focused on the study of master transcriptional regulators involved in energy, cholesterol and lipid metabolism and adipogenesis. Therefore, our experimental work aimed to investigate the possible hepatoprotective effects and safety of fatostatin, which is the inhibitor of sterol regulatory element binding proteins 1 and 2 (SREBP1/2), in preclinical dietary models of the MASLD progression. Pretreatment of primary hepatocytes with fatostatin improved in vitro lipotoxicity produced by palmitic acid. To induce MASLD-to-MASH progression in vivo, male C57BL6J mice received a special western-type atherogenic diet with fructose and glucose in drinking water for 12 weeks. Despite the simultaneous administration of the diet to mice, an additional 4-week fatostatin treatment significantly improved the oral glucose tolerance test and reduced body, adipose tissue and liver weights, fasting glycemia, alkaline phosphatase, total cholesterol, liver conjugated dienes, nitrites and triglycerides, steatosis, and histopathological total MASLD activity score. These effects were related to the beneficial modulatory effect of fatostatin on liver expression of genes involved in lipid metabolism. Although fatostatin remarkably slowed the progression of MASLD, it produced elevated serum TNF-alpha, representing systemic inflammation, and severe skin adverse reactions similar to eczema, previously not reported. Therefore, we assume that liver-targeted specific inhibition of SREBP1/2 could be valuable in treating the progression of MASLD to MASH without concomitant skin toxicity.

• Klíčová slova
• Fatostatin, MASH, MASLD, Mouse, SREBP,
• MeSH
• hepatocyty účinky léků   metabolismus   patologie   MeSH
• játra účinky léků   patologie   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater MeSH
• progrese nemoci MeSH
• protein SREBP1 * antagonisté a inhibitory   metabolismus   MeSH
• protein SREBP2 * antagonisté a inhibitory   metabolismus   MeSH
• pyridiny MeSH
• spirosloučeniny * farmakologie   terapeutické užití   škodlivé účinky   MeSH
• thiazoly MeSH
• ztučnělá játra * farmakoterapie   patologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fatostatin MeSH Prohlížeč
• protein SREBP1 * MeSH
• protein SREBP2 * MeSH
• pyridiny MeSH
• spirosloučeniny * MeSH
• Srebf1 protein, mouse MeSH Prohlížeč
• thiazoly MeSH

BACKGROUND: Vibrational and chiroptical spectroscopy of blood plasma is an advanced experimental diagnostic approach that allows the identification of disease-specific molecular patterns. This study aimed to test its potential to distinguish between different stages of metabolic dysfunction-associated steatotic liver disease (MASLD) including liver fibrosis. METHODS: We analyzed blood plasma samples from 29 patients with metabolic dysfunction-associated steatohepatitis (MASH) and 24 MASLD patients with simple steatosis using Fourier-transform infrared (FTIR) spectroscopy, Raman spectroscopy and electronic circular dichroism (ECD) spectroscopy to distinguish: (i) MASH; (ii) MASH with moderate to advanced fibrosis; and (iii) overall fibrosis. RESULTS: FTIR spectroscopy distinguished MASH from simple steatosis with a sensitivity of 73% and a specificity of 92%, with an area under the receiver operating characteristic curve (AUROC) of 0.92, p < 0.001. In addition, FTIR spectroscopy identified MASH with moderate to advanced fibrosis (F2-3) from MASH/steatosis with no to mild fibrosis (F0-1) with a sensitivity of 87% and specificity of 78% (AUROC 0.91, p < 0.001). Furthermore, regardless of the MASH/steatosis diagnosis, fibrosis (F1-3) was distinguished from F0 by the combination of data from the three spectroscopic methods with a sensitivity of 79% and a specificity of 88% (AUROC 0.91, p < 0.001). Both FTIR and Raman spectroscopy alone discriminated all target groups with an AUROC > 0.82. CONCLUSIONS: This pilot study revealed the potential of blood plasma spectroscopy to identify and differentiate patients with various stages of MASLD.

• Klíčová slova
• Chiroptical spectroscopy, Electronic circular dichroism spectroscopy (ECD), Fourier-transform infrared (FTIR) spectroscopy, Liver fibrosis, Metabolic dysfunction-associated steatohepatitis (MASH), Metabolic dysfunction-associated steatotic liver disease (MASLD), Noninvasive diagnostics, Raman spectroscopy, Simple steatosis, Vibrational spectroscopy,
• MeSH
• cirkulární dichroismus MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• jaterní cirhóza krev   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolické nemoci * krev   komplikace   diagnóza   MeSH
• Ramanova spektroskopie MeSH
• ROC křivka MeSH
• senioři MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• ztučnělá játra * krev   diagnóza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Tacrine, the first approved drug against Alzheimer's disease (AD), was withdrawn from clinical use due to serious adverse effects. The main concern was the human hepatotoxicity, stemming probably from the liver biotransformation and clinically manifested as hepatocellular necrosis, and lobular hepatitis. Concerning the biotransformation, 7-OH-tacrine metabolite is generally suspected of being a precursor of toxic quinone methide, which binds to intracellular -SH proteins and/or depletes intracellular glutathione, and by that probably causes the hepatotoxicity. However, to study these toxic effects, proper animal model is needed to monitor the interspecies differences of metabolism. To fully describe in vivo ADMET parameters of tacrine, five experimental pigs (Sus scrofa f. domestica), as the most physiologically human-like in vivo model showing similar tacrine biotransformation, were used. We studied tacrine and its metabolites ADMET characteristics after both acute i.g. single dose and chronic 42 days p.o daily dose administration of 200 mg of tacrine. Tacrine and its two major metabolites show Tmax in plasma of 360 min, so the absorption is much slower than in human (Tmax = 120 min) and are primarily distributed to the gastro-intestinal tract and CNS. Furthermore, due to the lower activity of CYP1A2 in pigs, tacrine is biotransformed much less efficiently than in humans. This study showed that tacrine accumulates only in adipose tissue, and organ histology and plasma biochemistry assessment revealed no signs of hepatotoxicity even after chronic tacrine administration. Pigs are therefore an unsuitable human-like animal model for evaluating tacrine toxicity.

• Klíčová slova
• Biotransformation, Distribution, Hepatotoxicity, Pig model, Tacrine,
• MeSH
• biotransformace MeSH
• cholinesterasové inhibitory toxicita   farmakokinetika   MeSH
• játra * účinky léků   metabolismus   patologie   MeSH
• lékové postižení jater * metabolismus   patologie   MeSH
• lidé MeSH
• prasata MeSH
• Sus scrofa MeSH
• takrin * farmakokinetika   toxicita   metabolismus   analogy a deriváty   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• takrin * MeSH

Sarcopenia, characterized by skeletal muscle atrophy, was previously considered age-related; however, it is also associated with other diseases. Nonalcoholic fatty liver disease (NAFLD) is known to cause sarcopenia, and its complications have been reported to affect prognosis. The intestinal microbiota of patients with NAFLD or sarcopenia has been found to be altered compared to that of healthy individuals. However, the alterations that occur when both diseases coexist in humans or experimental animals remain unclear. Therefore, this study aimed to determine the intestinal microbiota changes associated with NAFLD with sarcopenia in SHRSP5/Dmcr rats at the time of concomitant disease. Fecal samples were collected from the rectum of SHRSP5/Dmcr rats fed a normal diet (non-NAFLD and non-Sarcopenia, n = 5) or a high-fat and high-cholesterol diet (NAFLD and Sarcopenia, n = 5) for 20 weeks, and subjected to 16S rRNA analysis. In the NAFLD and sarcopenia group, the diversity of the intestinal microbiota was reduced; further, the bacterial species reported in patients with NAFLD or sarcopenia were also changed. At the family level, the abundances of Akkermansiaceae, Bacteroidaceae, and Tannerellaceae were significantly higher whereas Ruminococcaceae and Lactobacillaceae were decreased in the NAFLD and sarcopenia group. At the genus level, the abundances of Akkermansia, Bacteroides, Ruminococcus, and Parabacteroides were significantly higher whereas the abundance of Lactobacillus was significantly decreased in the NAFLD and sarcopenia group. Overall, these findings help improve the existing understanding regarding the intestinal microbiota changes observed in conditions where NASH and sarcopenia co-occur.

• Klíčová slova
• Bacteroides, Ruminococcus, Intestinal microbiota, Nonalcoholic steatohepatitis, Sarcopenia,
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) may be as high as 38% in the adult population with potential serious complications, multiple comorbidities and a high socioeconomic burden. However, there is a general lack of awareness and knowledge about MASLD and its progressive stages (metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis). Therefore, MASLD is still far underdiagnosed. The 'Global Research Initiative for Patient Screening on MASH' (GRIPonMASH) consortium focuses on this unmet public health need. GRIPonMASH will help (primary) healthcare providers to implement a patient care pathway, as recommended by multiple scientific societies, to identify patients at risk of severe MASLD and to raise awareness. Furthermore, GRIPonMASH will contribute to a better understanding of the pathophysiology of MASLD and improved identification of diagnostic and prognostic markers to detect individuals at risk. METHODS: This is a prospective multicentre observational study in which 10 000 high-risk patients (type 2 diabetes mellitus, obesity, metabolic syndrome or hypertension) will be screened in 10 European countries using at least two non-invasive tests (Fibrosis-4 index and FibroScan). Blood samples and liver biopsy material will be collected and biobanked, and multiomics analyses will be conducted. ETHICS AND DISSEMINATION: The study will be conducted in compliance with this protocol and applicable national and international regulatory requirements. The study initiation package is submitted at the local level. The study protocol has been approved by local medical ethical committees in all 10 participating countries. Results will be made public and published in scientific, peer-reviewed, international journals and at international conferences. REGISTRATION DETAILS: NCT05651724, registration date: 15 Dec 2022.

• Klíčová slova
• EPIDEMIOLOGY, Gastroenterology, Hepatology, INTERNAL MEDICINE, Mass Screening,
• MeSH
• diabetes mellitus 2. typu komplikace   MeSH
• jaterní cirhóza diagnóza   MeSH
• lidé MeSH
• metabolický syndrom komplikace   MeSH
• multicentrické studie jako téma MeSH
• nealkoholová steatóza jater * diagnóza   MeSH
• plošný screening * metody   MeSH
• prospektivní studie MeSH
• výzkumný projekt MeSH
• ztučnělá játra * diagnóza   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH

Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholestasis for 4 wk. The content of individual BAs in the plasma, liver, bile, intestine, and feces was measured using the LC-MS method alongside the analysis of liver phenotype and related executive and regulatory pathways. The DMF slowed down the progression of DDC-induced liver fibrosis by suppressing hepatic stellate cell and macrophage activation and by reducing c-Jun N-terminal kinase phosphorylation. Notably, DMF reduced BA cumulation in the plasma and liver of cholestatic mice by increasing BA fecal excretion via their reduced Bacteroidetes phyla-mediated deconjugation in the intestine. In addition, DMF was identified as the antagonist of the mouse farnesoid X receptor in enterocytes. In conclusion, DMF alleviates DDC-induced cholestatic liver injury through pleiotropic action leading to significant anti-inflammatory and antifibrotic activity of the agent. In addition, DMF mitigates BA retention in the liver and plasma by increasing their fecal excretion in cholestatic mice. These findings suggest that DMF warrants further investigation as a potential therapeutic agent for human chronic fibrosing cholestatic liver disorders.NEW & NOTEWORTHY Chronic cholestatic cholangiopathies present a therapeutic challenge due to their complex pathophysiology, where the accumulation of bile acids plays a crucial role. In this study, we found that dimethyl fumarate attenuated cholestatic liver damage in a murine model through its significant anti-inflammatory and antifibrotic activity supported by reduced bile acid accumulation in the plasma and liver via their increased fecal excretion.

• Klíčová slova
• 3, 4-dihydrocollidine (DDC), 5-diethoxycarbonyl-1, bile acids, cholestasis, dimethyl fumarate, liver fibrosis,
• MeSH
• cholestáza * farmakoterapie   metabolismus   chemicky indukované   MeSH
• dimethyl fumarát * farmakologie   terapeutické užití   MeSH
• jaterní cirhóza * metabolismus   farmakoterapie   patologie   etiologie   MeSH
• jaterní hvězdicovité buňky účinky léků   metabolismus   MeSH
• játra * metabolismus   účinky léků   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• žlučové kyseliny a soli * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dimethyl fumarát * MeSH
• žlučové kyseliny a soli * MeSH

Accumulation of extracellular matrix (ECM) in liver fibrosis is associated with changes in protein abundance and composition depending upon etiology of the underlying liver disease. Current efforts to unravel etiology-specific mechanisms and pharmacological targets rely on several models of experimental fibrosis. Here, we characterize and compare dynamics of hepatic proteome remodeling during fibrosis development and spontaneous healing in experimental mouse models of hepatotoxic (carbon tetrachloride [CCl4] intoxication) and cholestatic (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] feeding) injury. Using detergent-based tissue extraction and mass spectrometry, we identified compartment-specific changes in the liver proteome with detailed attention to ECM composition and changes in protein solubility. Our analysis revealed distinct time-resolved CCl4 and DDC signatures, with identified signaling pathways suggesting limited healing and a potential for carcinogenesis associated with cholestasis. Correlation of protein abundance profiles with fibrous deposits revealed extracellular chaperone clusterin with implicated role in fibrosis resolution. Dynamics of clusterin expression was validated in the context of human liver fibrosis. Atomic force microscopy of fibrotic livers complemented proteomics with profiles of disease-associated changes in local liver tissue mechanics. This study determined compartment-specific proteomic landscapes of liver fibrosis and delineated etiology-specific ECM components, providing thus a foundation for future antifibrotic therapies.

Alcoholism or chronic conditions like hepatitis damage the liver. Over time, scar tissue builds up in the liver, causing cirrhosis. The scaring results from the liver’s repeated attempts to repair itself by creating more structural proteins called extracellular matrix proteins. A buildup of these scaffolding proteins leads to tissue stiffening or fibrosis. Fibrosis may heal in some cases but in others, it may progress to cirrhosis, liver cancer or liver failure. Learning more about these processes may help scientists and clinicians understand why fibrosis is reversible in some cases but not others. It may also allow them to develop treatments that can treat or reverse fibrosis and prevent cirrhosis, liver cancer, or liver failure. The first step is studying how fibrosis occurs in mouse models that mimic different types of liver disease. For example, repetitive ingestion of a toxic substance, such as alcohol, can cause one type of liver disease. However, slowing or stalling bile flow through the biliary system (the liver, gallbladder, and bile ducts), leads to a different type of chronic liver injury. Jirouskova et al. identify an extracellular protein called clusterin that may help heal fibrosis. The experiments used mouse models of two different types of liver disease. One mimicked liver disease caused by repetitive toxin injury, and the other modelled liver disease caused by chronic stalling of the bile flow in the liver (cholestasis). In the experiments, Jirouskova et al. looked at all the proteins made in each type of liver disease as the animals developed fibrosis or their fibrosis resolved. They also studied extracellular matrix proteins and how they affected molecular signaling in the liver tissue. The experiments revealed different patterns of protein production and healing in the different types of liver disease. The animals with liver diseases caused by chronic cholestatic injury were less likely to heal their livers and showed potential to progress to liver cancer. Production of the clusterin protein was connected with better liver recovery from toxic injuries. Jirouskova et al. provide a comprehensive map of all the proteins produced over the course of liver fibrosis progression and healing in two different animal models of liver disease. Scientists and clinicians may use this information to study liver disease types. It may also one day help them personalize patient's therapies. The experiments show that extracellular matrix proteins are essential contributors to fibrosis and key signaling agents in liver disease. This may make them good targets for new therapies. Boosting clusterin production may be one approach to promoting liver recovery. More studies are needed to confirm this before such therapies can be developed and tested in humans.

• Klíčová slova
• atomic force microscopy, clusterin, collagen deposits, human, mass spectrometry, matrisome, medicine, mouse,
• MeSH
• chlorid uhličitý toxicita   MeSH
• cholestáza * metabolismus   chemicky indukované   patologie   MeSH
• extracelulární matrix metabolismus   MeSH
• jaterní cirhóza * metabolismus   patologie   chemicky indukované   MeSH
• játra * patologie   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteom * metabolismus   analýza   MeSH
• proteomika MeSH
• pyridiny MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3,5-diethoxycarbonyl-1,4-dihydrocollidine MeSH Prohlížeč
• chlorid uhličitý MeSH
• proteom * MeSH
• pyridiny MeSH

BACKGROUND: Atherosclerotic cardiovascular diseases (ACVDs), a condition characterised by lipid accumulation in arterial walls, which is often exacerbated by chronic inflammation disorders, is the major cause of mortality and morbidity worldwide. Colchicine, with its first medicinal use in ancient Egypt, is an inexpensive drug with anti-inflammatory properties. However, its role in primary prevention of ACVDs in the general population remains unknown. OBJECTIVES: To assess the clinical benefits and harms of colchicine as primary prevention of cardiovascular outcomes in the general population. SEARCH METHODS: We searched the Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, Web of Science, and LILACS. We searched ClinicalTrials.gov and WHO ICTRP for ongoing and unpublished studies. We also scanned the reference lists of relevant included studies, reviews, meta-analyses, and health technology reports to identify additional studies. There were no limitations on language, date of publication, or study setting. The search results were updated on 31 May 2023. SELECTION CRITERIA: Randomised controlled trials (RCTs) in any setting, recruiting adults without pre-existing cardiovascular disease. We included trials that compared colchicine versus placebo, non-steroidal anti-inflammatory drugs, corticosteroids, immunomodulating drugs, or usual care. Our primary outcomes were all-cause mortality, non-fatal myocardial infarction, stroke, and adverse events. DATA COLLECTION AND ANALYSIS: Two or more review authors independently selected studies, extracted data, and performed risk of bias and GRADE assessments. MAIN RESULTS: We identified 15 RCTs (1721 participants randomised; 1412 participants analysed) with follow-up periods ranging from 4 to 728 weeks. The intervention was oral colchicine compared with placebo, immunomodulating drugs, or usual care or no treatment. Due to biases and imprecision, the evidence was very uncertain for all outcomes. All trials but one had a high risk of bias. Five out of seven meta-analyses included fewer than six trials (71.4%). The objectives of the review were to assess cardiovascular outcomes in the general population, but many of the included trials focused on liver disease. Colchicine compared to placebo Colchicine may reduce all-cause mortality compared to placebo in primary prevention, but the evidence is very uncertain (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.51 to 0.91; 6 studies, 463 participants; very low-certainty evidence; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 6 to 67). Colchicine may result in little to no difference in non-fatal myocardial infarction, but the evidence is very uncertain (RR 0.87, 95% CI 0.41 to 1.82; 1 study, 100 participants; very low-certainty evidence). Colchicine may not reduce the incidence of stroke, but the evidence is very uncertain (RR 2.43, 95% CI 0.67 to 8.86; 1 study, 100 participants; very low-certainty evidence). Regarding adverse events, colchicine may increase the incidence of diarrhoea (RR 3.99, 95% CI 1.44 to 11.06; 8 studies, 605 participants; very low-certainty evidence; number needed to treat for an additional harmful outcome (NNTH) 10, 95% CI 6 to 17), and may have little to no effect on neurological outcomes such as seizure or mental confusion (RR 0.72, 95% CI 0.31 to 1.66; 2 studies, 155 participants; very low-certainty evidence), but the evidence is very uncertain. The effect of colchicine on cardiovascular mortality is also very uncertain (RR 1.27, 95% CI 0.03 to 62.43; 2 studies, 160 participants; very low-certainty evidence). Colchicine may not reduce post-cardiac procedure atrial fibrillation, but the evidence is very uncertain (RR 0.74, 95% CI 0.25 to 2.19; 1 study, 100 participants). We found no trials reporting on pericardial effusion, peripheral artery disease, heart failure, or unstable angina. Colchicine compared to methotrexate (immunomodulating drug) Colchicine may result in little to no difference in all-cause mortality compared to methotrexate, but the evidence is very uncertain (RR 0.42, 95% CI 0.12 to 1.51; 1 study, 85 participants; very low-certainty evidence). We found no trials reporting other cardiovascular outcomes or adverse events for this comparison. Colchicine compared to usual care or no treatment The evidence is very uncertain about the effect of colchicine compared with usual care on all-cause mortality in primary prevention (RR 1.07, 95% CI 0.90 to 1.27; 2 studies, 729 participants; very low-certainty evidence). Regarding adverse events, colchicine may increase the incidence of diarrhoea compared to usual care, but the evidence is very uncertain (RR 3.32, 95% CI 1.56 to 7.03; 2 studies, 729 participants; very low-certainty evidence; NNTH 18, 95% CI 12 to 42). No trials reported other cardiovascular outcomes for this comparison. AUTHORS' CONCLUSIONS: This Cochrane review evaluated the clinical benefits and harms of using colchicine for the primary prevention of cardiovascular events in the general population. Comparisons were made against placebo, immunomodulating medications, or usual care or no treatment. However, the certainty of the evidence for the predefined outcomes was very low, highlighting the pressing need for high-quality, rigorous studies to ascertain colchicine's clinical impact definitively. We identified numerous biases and inaccuracies in the included studies, limiting their generalisability and precluding a conclusive determination of colchicine's efficacy in preventing cardiovascular events. The existing evidence regarding colchicine's potential cardiovascular benefits or harms for primary prevention is inconclusive owing to the limitations inherent in the current studies. More robust clinical trials are needed to bridge this evidence gap effectively.

• MeSH
• antiflogistika nesteroidní terapeutické užití   MeSH
• antiflogistika * terapeutické užití   škodlivé účinky   MeSH
• ateroskleróza prevence a kontrola   mortalita   MeSH
• cévní mozková příhoda prevence a kontrola   epidemiologie   mortalita   MeSH
• dospělí MeSH
• infarkt myokardu prevence a kontrola   epidemiologie   MeSH
• kardiovaskulární nemoci * prevence a kontrola   mortalita   MeSH
• kolchicin * terapeutické užití   škodlivé účinky   MeSH
• lidé MeSH
• placebo terapeutické užití   MeSH
• příčina smrti MeSH
• primární prevence * metody   MeSH
• randomizované kontrolované studie jako téma MeSH
• zkreslení výsledků (epidemiologie) MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• antiflogistika * MeSH
• kolchicin * MeSH
• placebo MeSH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

• Klíčová slova
• Antioxidant enzyme, Catalytic activity, Expression, Glutathione, Metabolic dysfunction-associated steatotic liver disease,
• MeSH
• antioxidancia * metabolismus   MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ztučnělá játra * metabolismus   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia * MeSH
• reaktivní formy kyslíku MeSH