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Prediction of carotid intima–media thickness in obese patients with low prevalence of comorbidities by serum copper bioavailability
Abstract
Background:
Western societies, with growing prevalence, suffer from various metabolic diseases like obesity, hepatic steatosis, better defined as non-alcoholic fatty liver disease (NAFLD), or cardiovascular (CV) diseases that are strictly linked each other. The association of their occurrence with the altered homeostasis of metals is an intriguing issue. Copper in particular was identified as key player in various metabolic derangements. On these bases we aimed at investigating the possible association of serum copper levels with an indicator of early CV risk as the Intima-Media Tickess (IMT) of carotid artery and its predictive value in a selected population of obese patients.
Methods:
We performed a cross-sectional study recruiting 100 obese patients characterised by a low prevalence of co-morbidities. Ultrasound (US) investigation for hepatic steatosis and IMT evaluation was performed. Serum samples were collected and then analysed through atomic absorption spectrometry to evaluate their copper content. Possible correlations between copper bioavailabilty and biochemical, clinical and anthropometric characteristics of patients were sought.
Results:
Age negatively predicted copper serum levels of patients (p=.009). However, the most interesting finding is the negative prediction of IMT by the copper serum levels (t -2.23, P=0.028, Least Absolute Deviations Regression). Factor analysis confirmed the afore mentioned inverse correlation and highlighted the strong inverse correlation between smoking and copper serum levels.
Conclusion:
Our data show that an altered copper bioavailability predicts early atherosclerosis as main CV risk in obese patients with hepatic steatosis detected by US, shedding some light in this pathological scenario.
... Moreover, an increase in serum copper levels among post-MI patients was found to have considerable diagnostic value for the occurrence of MI [53]. Furthermore, altered copper bioavailability is negatively correlated with carotid intimamedia thickness (IMT), which may serve as a reliable predictor for early atherosclerosis in patients with obesity [54]. Furthermore, serum copper concentrations differ among patients with different carotid atherosclerotic plaque morphologies. ...
... Italy, Tarantino et al.[54] 100 obese patients who had a low prevalence of comorbidities.Altered copper bioavailability was negatively associated with carotid IMT (t = −2.23, P = 0.028) and may predict early atherosclerosis in obese patients. ...
Copper is an essential micronutrient that plays a pivotal role in numerous physiological processes in virtually all cell types. Nevertheless, the dysregulation of copper homeostasis, whether towards excess or deficiency, can lead to pathological alterations, such as atherosclerosis. With the advent of the concept of copper-induced cell death, termed cuproptosis, researchers have increasingly focused on the potential role of copper dyshomeostasis in atherosclerosis. In this review, we provide a broad overview of cellular and systemic copper metabolism. We then summarize the evidence linking copper dyshomeostasis to atherosclerosis and elucidate the potential mechanisms underlying atherosclerosis development in terms of both copper excess and copper deficiency. Furthermore, we discuss the evidence for and mechanisms of cuproptosis, discuss its interactions with other modes of cell death, and highlight the role of cuproptosis-related mitochondrial dysfunction in atherosclerosis. Finally, we explore the therapeutic strategy of targeting this novel form of cell death, aiming to provide some insights for the management of atherosclerosis.
... This observation underscores the paradoxical role of copper in liver disease, as both deficiencies and excesses of copper could lead to metabolic dysfunction [106]. Notably, altered copper bioavailability, which has been shown to predict early atherosclerosis, serves as a major cardiovascular risk factor in obese patients with hepatic steatosis detected by ultrasound [107]. ...
Background
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and its prevalence has risen sharply. However, whether nutrition, dietary strategies, exercise, lifestyle and environment have preventive value for NAFLD remains unclear.
Methods
Through searching 4 databases (PubMed, Web of Science, Embase and the Cochrane Library) from inception to January 2025, we selected studies about nutrition, dietary strategies, exercise, lifestyle and environment in the prevention of NAFLD and conducted a narrative review on this topic.
Results
Reasonable nutrient intake encompassing macronutrients and micronutrients have an independent protective relationship with NAFLD. Besides, proper dietary strategies including mediterranean diet, intermittent fasting diet, ketogenic diet, and dietary approaches to stop hypertension diet have their inhibitory effects on the developmental process of NAFLD. Moreover, right exercises including walking, jogging, bicycling, and swimming are recommended for the prevention of NAFLD because they could effectively reduce weight, which is an important risk factor for NAFLD, and improve liver function. In addition, embracing a healthy lifestyle including reducing sedentary behavior, not smoking, sleeping well and brushing teeth regularly is integral since it not only could reduce the risk of NAFLD but also significantly contribute to overall prevention and control. Finally, the environment, including the social and natural environments, plays a potential role in NAFLD prevention.
Conclusion
Nutrition, dietary strategies, exercise, lifestyle and environment play an important role in the prevention of NAFLD. Moreover, this review offers comprehensive prevention recommendations for people at high risk of NAFLD.
... The intima-media thickness (IMT) represents a well-known indicator of subclinical atherosclerosis, the principal cause of death in relation to MASLD [47], and also acts as a prognostic parameter for the assessment of cardiovascular risk [48]. It is highlighted that reduced Cu bioavailability is inversely associated with IMT values in specific populations [49]. Given the high prevalence of Mg deficiency in MASLD patients, coupled with the protective effect of Cu itself, we suppose that diminished Mg-Cu collaboration may account for worse clinical outcomes ( Figure 1). ...
Magnesium (Mg), which is predominantly present in cells as a micronutrient, is involved in numerous vital physiological processes, such as DNA repair and energy metabolism. Mg deficiency has been reported to contribute toward the advent and progression of a variety of liver diseases; in particular, these two pathological entities may synergistically act. Given the significant impact and increasing burden of liver diseases on global healthcare resources and economic expenditure, it is tempting to manage Mg insufficiency as novel promising therapeutic strategies. In this review, we comprehensively elaborate on the complicated relationship between Mg deficiency and several contextual liver diseases, with concentrating on the underlying molecular mechanisms.
... It should be underlined that oxidative stress is a factor contributing to the progression of NAFLD, while antioxidant molecules such as silymarin, silybin or silibinin, pentoxifylline, resveratrol, vitamins A, C, and E are potential therapeutic agents against NAFLD [50]. Recent data show that impaired copper bioavailability foretells early atherosclerosis in obese patients with hepatic steatosis detected by US, i.e., NAFLD [51]. This main cardiovascular (CV) risk will be dealt with below. ...
The aim of this review was to gather pieces of information from available critically evaluated published articles concerning any interplay in which the spleen could be involved. For many years, the spleen has been alleged as an unnecessary biological structure, even though splenomegaly is an objective finding of many illnesses. Indeed, the previous opinion has been completely changed. In fact, the spleen is not a passive participant in or a simple bystander to a relationship that exists between the immune system and other organs. Recently, it has been evidenced in many preclinical and clinical studies that there are close associations between the spleen and other parts of the body, leading to various spleen–organ axes. Among them, the gut–spleen axis, the liver–spleen axis, the gut–spleen–skin axis, the brain–spleen axis, and the cardio-splenic axis are the most explored and present in the medical literature. Such recent sources of evidence have led to revolutionary new ideas being developed about the spleen. What is more, these observations may enable the identification of novel therapeutic strategies targeted at various current diseases. The time has come to make clear that the spleen is not a superfluous body part, while health system operators and physicians should pay more attention to this organ. Indeed, much work remains to be performed to assess further roles that this biological structure could play.
... There is growing evidence that dysregulated copper metabolism and copper excess or deficiency are associated with AS, and extensive research has revealed a correlation between elevated copper levels and cardiovascular disease (36). One study found that copper bioavailability was negatively correlated with carotid intima-media thickness and that CAS was a reliable predictor of early AS in obese patients (37). In addition, Nadina found increased copper levels in CAS plaques, and Nebojša demonstrated that serum copper concentrations also varied in patients with different types of CAS plaques, especially in patients with hemorrhagic plaques of CAS, which were significantly higher than in patients with calcified plaques (38). ...
Background
Atherosclerosis is a leading cause of cardiovascular disease worldwide, while carotid atherosclerosis (CAS) is more likely to cause ischemic cerebrovascular events. Emerging evidence suggests that cuproptosis may be associated with an increased risk of atherosclerotic cardiovascular disease. This study aims to explore the potential mechanisms linking cuproptosis and CAS.
Methods
The GSE100927 and GSE43292 datasets were merged to screen for CAS differentially expressed genes (DEGs) and intersected with cuproptosis-related genes to obtain CAS cuproptosis-related genes (CASCRGs). Unsupervised cluster analysis was performed on CAS samples to identify cuproptosis molecular clusters. Weighted gene co-expression network analysis was performed on all samples and cuproptosis molecule clusters to identify common module genes. CAS-specific DEGs were identified in the GSE100927 dataset and intersected with common module genes to obtain candidate hub genes. Finally, 83 machine learning models were constructed to screen hub genes and construct a nomogram to predict the incidence of CAS.
Results
Four ASCRGs (NLRP3, SLC31A2, CDKN2A, and GLS) were identified as regulators of the immune infiltration microenvironment in CAS. CAS samples were identified with two cuproptosis-related molecular clusters with significant biological function differences based on ASCRGs. 220 common module hub genes and 1,518 CAS-specific DEGs were intersected to obtain 58 candidate hub genes, and the machine learning model showed that the Lasso + XGBoost model exhibited the best discriminative performance. Further external validation of single gene differential analysis and nomogram identified SGCE, PCDH7, RAB23, and RIMKLB as hub genes; SGCE and PCDH7 were also used as biomarkers to characterize CAS plaque stability. Finally, a nomogram was developed to assess the incidence of CAS and exhibited satisfactory predictive performance.
Conclusions
Cuproptosis alters the CAS immune infiltration microenvironment and may regulate actin cytoskeleton formation.
... Second, the data in this study came from the Chinese metal-exposed workers cohort 61 , and the Jinchang cohort had higher levels of urinary metals compared with the general occupational population. There is evidence that heavy metals have a lipotropic effect, resulting in obesity and increasing the risk of NAFLD and CVD 62,63 , e.g., serum copper bioavailability can help predict the risk of CVD in obese NAFLD patients 64 . However, the effect of heavy metals on the results of the study was not considered in this study for the time being. ...
Backgrounds
This investigation seeks to explore the correlation between nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs), and to to provide evidence for the prevention and treatment of CVDs.
Methods
This study utilized data from the Jinchang cohort platform, including 19,399 participants without pre-existing major CVDs. Based on the general population and gender stratification, Cox models were used to analyze the risk of NAFLD for CVDs. The combined effect of NAFLD and different obesity indicators on CVDs was analyzed by additive and multiplicative interaction models and subgroups.
Results
There were 3129 NAFLD patients out of 19399 subjects, and 723 (23.11%) of them had the CVD. After adjusting for multiple confounding factors, the Cox model revealed a 1.17-fold increase in the risk of CVDs among patients with NAFLD compared to those without NAFLD. Moreover, there was no notable disparity in CVDs risk among most NAFLD patients at the same level of obesity. The results indicated no additive interaction between NAFLD and obesity concerning CVDs risk, but rather a positive multiplicative interaction. Using the normal population as a reference, it was found that people with both obesity and NAFLD significantly increased the risk of developing CVDs, with HRs and 95% CIs of 1.790 (1.508, 2.126), 1.356 (1.213, 1.517), and 1.807 (1.503, 2.174), respectively, for BMI, WC, and the combination of BMI and WC.
Conclusions
NAFLD and obesity are independent risk factors for CVDs. The synergy of obesity and NAFLD implies that NAFLD patients should control weight gain. Larger BMI and WC values may increase the CVDs risk for NAFLD patients, especially women.
... Another study with 100 subjects showed the different results that elevated copper in serum was associated with decreased carotid intima-media thickness. 32 Of note, these 2 studies did not adjust for relevant confounding factors, as well as having a small sample size. Additionally, compared with plaque presence, the predictive value of carotid intima-media thickness in cardiovascular risk estimation is under debate by experts, 33 and the American College of Cardiology/ American Heart Association advised against measuring carotid intima-media thickness for the risk evaluation for ischemic cardiovascular events. ...
Background
Copper exposure is reported to be associated with increased risk of stroke. However, the association of copper exposure with subclinical carotid atherosclerosis remains unclear.
Methods and Results
This observational study included consecutive participants from Xinqiao Hospital between May 2020 and August 2021. Blood metals were measured using inductively coupled plasma mass spectrometry and carotid atherosclerosis was assessed using ultrasound. Modified Poisson regression was performed to evaluate the associations of copper and other metals with subclinical carotid plaque presence. Blood metals were analyzed as categorical according to the quartiles. Multivariable models were adjusted for age, sex, body mass index, education, smoking, drinking, hypertension, diabetes, dyslipidemia, estimated glomerular filtration rate, and coronary artery disease history. Bayesian Kernel Machine Regression was conducted to evaluate the overall association of metal mixture with subclinical carotid plaque presence. One thousand five hundred eighty‐five participants were finally enrolled in our study, and carotid plaque was found in 1091 subjects. After adjusting for potential confounders, metal‐progressively‐adjusted models showed that blood copper was positively associated with subclinical carotid plaque (relative risk according to comparing quartile 4 to quartile 1 was 1.124 [1.021–1.238], relative risk according to per interquartile increment was 1.039 [1.008–1.071]). Blood cadmium and lead were also significantly associated with subclinical carotid plaque. Bayesian Kernel Machine Regression analyses suggested a synergistic effect of copper–cadmium–lead mixture on subclinical carotid plaque presence.
Conclusions
Our findings identify copper as a novel risk factor of subclinical carotid atherosclerosis and show the potential synergistic proatherogenic effect of copper, cadmium, and lead mixture.
... Notably, an altered copper bioavailability, as evidenced by copper serum levels, predicts early atherosclerosis as the main cardiovascular risk assessed as the intima-media thickness of carotid artery in obese, non-Wilson disease patients with hepatic steatosis detected by ultrasound [231]. These results led to the assumption that copper may play a contributory role in the development of atherosclerosis connected with fatty liver diseases. ...
Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu²⁺ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber–Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.
... Notably, serum copper showed negative correlation with intima-media thickness, a noninvasive diagnostic tool for premature or subclinical AS identification, as well as functional and structural marker of this process. 39 In another study, bathocuproinedisulfonic treatment caused copper depletion, leading to depolarization of the mitochondrial membrane potential, increased levels of reactive oxygen species (ROS), oxidative stress induction, and decreased glutathione levels. These effects are similar to those of ox-LDL. ...
Ferroptosis has been confirmed to be associated with various diseases, but the relationship between ferroptosis and atherosclerosis (AS) remains unclear. Our research detailly clarified the roles of ferroptosis in three continuous and main pathological stages of AS respectively (injury of endothelial cells [ECs], adhesion of monocytes, and formation of foam cells). We confirmed that oxidized low‐density lipoprotein (ox‐LDL), the key factor in the pathogenesis of AS, strongly induced ferroptosis in ECs. Inhibition of ferroptosis repressed the adhesion of monocytes to ECs by inhibiting inflammation of ECs. Ferroptosis also participated in the formation of foam cells and lipids by regulating the cholesterol efflux of macrophages. Further research confirmed that ox‐LDL repressedthe activity of glutathione peroxidase 4 (GPX4), the classic lipid peroxide scavenger. Treatment of a high‐fat diet significantly induced ferroptosis in murine aortas and aortic sinuses, which was accompanied by AS lesions and hyperlipidemia. Treatment with ferroptosis inhibitors significantly reduced ferroptosis, hyperlipidemia, and AS lesion development. In conclusion, our research determined that ox‐LDL induced ferroptosis by repressing the activity of GPX4. Antiferroptosis treatment showed promising treatment effects in vivo. Ferroptosis‐associated indexes also showed promising diagnostic potential in AS patients.
... In a cross-sectional study that included 100 obese patients with hepatic steatosis detected by ultrasound, it was shown that an altered copper bioavailability predicts early atherosclerosis. 56 Moreover, older studies demonstrated that pancreatic fatty deposition is also accompanied by leukocyte infiltration, 57 although more recent ones did not corroborate these findings. 1 ...
Non-Alcoholic Fatty Pancreas disease (NAFPD), characterized by fat accumulation in pancreatic tissue, is an emerging clinical entity. However, the clinical associations, the underlying molecular drivers, and the pathophysiological mechanisms of NAFPD have not yet been characterized in detail. The NAFPD spectrum not only includes infiltration and accumulation of fat within and between pancreatic cells but also involves several inflammatory processes, dysregulation of physiological metabolic pathways, and hormonal defects. A deeper understanding of the underlying molecular mechanisms is key to correlate NAFPD with clinical entities including non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, atherosclerosis, as well as pancreatic cancer and pancreatitis. The aim of this review is to examine the pathophysiological mechanisms of NAFPD and to assess the possible causative/predictive risk factors of NAFPD-related clinical syndromes.
... (28) Copper is one of the essential components of the micronutrients (29) and has been reported to be involved in the progression of fatty liver diseases. (30) NAFLD patients have 50 % less hepatic copper content compared to subjects with unrelated liver injury. (31) TG level in the liver increasing to more than 5 % of liver weight or volume may cause hepatic steatosis. ...
Metabolic-associated fatty liver disease (MAFLD) has been proposed to replace the term non-alcoholic fatty liver disease (NAFLD) in 2020. The association between micronutrients and MAFLD has not been reported. Therefore, this study aims to explore the association between micronutrients intake and MAFLD. This was a cross-section study based on the National Health and Nutrition Examination Survey (NHANES). The dietary intake of copper, zinc, iron, and selenium was evaluated using the 24-h dietary recall interview. Logistic regression analysis was used to explore the association between micronutrients and MAFLD, and the results were shown as odds ratio (OR) with 95 % confidence intervals (CIs). A total of 5976 participants were finally included for analysis, with 3437 participants in the MAFLD group. After adjusting potential confounders, copper intake at quartile Q3 (OR = 0⋅68, 95 % CI 0⋅50, 0⋅93) and Q4 (OR = 0⋅60, 95 % CI 0⋅45, 0⋅80) was found to be associated with lower odds of MAFLD. Iron intake at Q2 (OR = 0⋅64, 95 % CI 0⋅45, 0⋅92) and Q3 (OR = 0⋅61, 95 % CI 0⋅41, 0⋅91) was associated with the lower odds of MAFLD. Our findings found that high intake of copper and adequate intake of iron were associated with MAFLD, which may provide guidance for the management of MAFLD.
... Elevated levels of copper ions in the serum and plaques of atherosclerotic patients have been demonstrated [3]. The data from the Giovanni Tarantino group shows that copper bioavailability is also a central factor in early atherosclerosis, as evidenced by the altered serum copper bioavailability predicting early atherosclerosis as the main cardiovascular risk in obese patients with a low prevalence of comorbidities [7]. Excess copper can be deposited in lysosomes, leading to cell death in human umbilical vein endothelial cells (HUVECs). ...
Atherosclerosis (AS) is a major contributor to morbidity and mortality worldwide. However, the molecular mechanisms and mediator molecules involved remain largely unknown. Copper, which plays an essential role in cardiovascular disease, has been suggested as a potential risk factor. Copper homeostasis is closely related to the occurrence and development of AS. Recently, a new cell death pathway called cuproptosis has been discovered, which is driven by intracellular copper excess. However, no previous studies have reported a relationship between cuproptosis and AS. In this study, we integrated bulk and single-cell sequencing data to screen and identify key cuproptosis-related genes in AS. We used correlation analysis, enrichment analysis, random forest, and other bioinformatics methods to reveal their relationships. Our findings report, for the first time, the involvement of cuproptosis-related genes FDX1, SLC31A1, and GLS in atherogenesis. FDX1 and SLC31A1 were upregulated, while GLS was downregulated in atherosclerotic plaque. Receiver operating characteristic curves demonstrate their potential diagnostic value for AS. Additionally, we confirm that GLS is mainly expressed in vascular smooth muscle cells, and SLC31A1 is mainly localized in macrophages of atherosclerotic lesions in experiments. These findings shed light on the cuproptosis landscape and potential diagnostic biomarkers for AS, providing further evidence about the vital role of cuproptosis in atherosclerosis progression.
... Separately, several studies have attempted to categorize comorbidity as being direct or inverse (Ibáñez, et al., 2014;Sánchez-Valle, et al., 2020;Tabarés-Seisdedos and Valderas, 2013;Tarantino, et al., 2018); that is, given an underlying disease, conditions that frequently co-occur at the population level are considered directly comorbid, while those with relatively few co-occurrences have inversely comorbid. Catalá-López et al. discovered that Alzheimer's disease can decrease the co-occurrence of cancers from meta-analysis with literatures (Catalá-López, et al., 2014). ...
Motivation
Understanding comorbidity is essential for disease prevention, treatment, and prognosis. In particular, insight into which pairs of diseases are likely or unlikely to co-occur may help elucidate the potential relationships between complex diseases. Here, we introduce the use of an inter-disease interactivity network to discover/prioritize comorbidities. Specifically, we determine disease associations by accounting for the direction of effects of genetic components shared between diseases, and categorize those associations as synergistic or antagonistic. We further develop a comorbidity scoring algorithm to predict whether diseases are more or less likely to co-occur in the presence of a given index disease. This algorithm can handle networks that incorporate relationships with opposite signs.
Results
We finally investigate inter-disease associations among 427 phenotypes in UK Biobank PheWAS data and predict the priority of comorbid diseases. The predicted comorbidities were verified using the UK Biobank inpatient electronic health records. Our findings demonstrate that considering the interaction of phenotype associations might be helpful in better predicting comorbidity.
Availability
The source code and data of this study are available at https://github.com/dokyoonkimlab/DiseaseInteractiveNetwork
Supplementary information
Supplementary data are available at Bioinformatics online.
... Nevertheless, it should be noted here that controversial findings have previously been published regarding the link between copper status and metabolic disorders, with some studies reporting lower levels of this metal in subjects with obesity [33] and related comorbidities, such as non-alcoholic fatty liver disease [34,35]. In this respect, is has been described that copper bioavailability is age-dependent [36], so differences in demographic characteristics might account in a large extent for the inconsistencies found in the literature. This further reinforce the need of using well-characterized cohorts and properly addressing inter-individual variability factors. ...
Metals are redox-active substances that participate in central biological processes and may be involved in a multitude of pathogenic events. However, considering the inconsistencies reported in the literature, further research is crucial to disentangle the role of metal homeostasis in childhood obesity and comorbidities using well-characterized cohorts and state-of-the-art analytical methods. To this end, we studied an observational population comprising children with obesity and insulin resistance, children with obesity without insulin resistance, and healthy control children. A multi-elemental approach based on the size-fractionation of metal species was applied to quantify the total content of various essential and toxic elements in plasma and erythrocyte samples, and to simultaneously investigate the metal fractions conforming the metalloproteome and the labile metal pool. The most important disturbances in childhood obesity were found to be related to elevated circulating copper levels, decreased content of plasmatic proteins containing chromium, cobalt, iron, manganese, molybdenum, selenium, and zinc, as well as the sequestration of copper, iron, and selenium within erythrocytes. Interestingly, these metal disturbances were normally exacerbated among children with concomitant insulin resistance, and in turn were associated to other characteristic pathogenic events, such as inflammation, oxidative stress, abnormal glucose metabolism, and dyslipidemia. Therefore, this study represents one-step further towards a better understanding of the involvement of metals in the crosstalk between childhood obesity and insulin resistance.
... Atherosclerosis is the principal CVD risk in obese patients with hepatic steatosis. According to a study by Tarantino et al. [203], altered copper bioavailability predicts early atherosclerosis. In vitro cupric ion-induced human low-density lipoprotein (LDL-c) peroxidation suggests that polyphenols may be beneficial for reducing CVD risk. ...
Wheat and rice play a vital role in human nutrition and food security. A better understanding of the potential health benefits associated with consuming these cereals, combined with studies by plant scientists and food chemists to view the entire food value chain from the field, pre and post-harvest processing, and subsequent “fork” consumption, may provide the necessary tools to optimize wheat and rice production towards the goal of better human health improvement and food security, providing tools to better adapt to the challenges associated with climate change. Since the available literature usually focuses on only one food chain segment, this narrative review was designed to address the identities and concentration of phenolics of these cereal crops from a farm-to-fork perspective. Wheat and rice genetics, phenolic databases, antioxidant properties, and potential health effects are summarized. These cereals contain much more than phenolic acids, having significant concentrations of flavonoids (including anthocyanins) and proanthocyanidins in a cultivar-dependent manner. Their potential health benefits in vitro have been extensively studied. According to a number of in vivo studies, consumption of whole wheat, wheat bran, whole rice, and rice bran may be strategies to improve health. Likewise, anthocyanin-rich cultivars have shown to be very promising as functional foods
... Chelation therapy and zinc salts are two treatments that reverse copper overload through separate methods. A study investigating the association between the bioavailability of copper and atherosclerosis determined that the baseline level of copper can be extrapolated as an indicator for the early detection of atherosclerosis [119] In some circumstances, liver transplantation is also recommended. Clinical trials for new drugs, such as tetrathiomolybdate salts, are now underway, and animal models are being used to evaluate genetic treatments [120]. ...
Simple Summary
Metabolic disorders (MD) are a challenge to healthcare systems; the emergence of the modern socio-economic system has led to a profound change in lifestyles in terms of dietary habits, exercise regimens, and behavior, all of which complement the genetic factors associated with MD. Diabetes Mellitus and Familial hypercholesterolemia are two of the 14 most widely researched MD, as they pose the greatest challenge to the public healthcare system and have an impact on productivity and the economy. Research findings have led to the development of new therapeutic molecules for the mitigation of MD as well as the invention of experimental strategies, which target the genes themselves via gene editing and RNA interference. Although these approaches may herald the emergence of a new toolbox to treat MD, the current therapeutic approaches still heavily depend on substrate reduction, dietary restrictions based on genetic factors, exercise, and the maintenance of good mental health. The development of orphan drugs for the less common MD such as Krabbe, Farber, Fabry, and Gaucher diseases, remains in its infancy, owing to the lack of investment in research and development, and this has driven the development of personalized therapeutics based on gene silencing and related technologies.
Abstract
Advances in data acquisition via high resolution genomic, transcriptomic, proteomic and metabolomic platforms have driven the discovery of the underlying factors associated with metabolic disorders (MD) and led to interventions that target the underlying genetic causes as well as lifestyle changes and dietary regulation. The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), Niemann-Pick disease, Phenylketonuria (PKU), Porphyria, Tay-Sachs disease, Wilson’s disease, Familial hypertriglyceridemia (F-HTG) and Galactosemia based on genome wide association studies, epigenetic factors, transcript regulation, post-translational genetic modifications and biomarker discovery through metabolomic studies. We will delve into the current approaches being undertaken to analyze metadata using bioinformatic approaches and the emerging interventions using genome editing platforms as applied to animal models.
... The beneficial effects of wholegrain on blood pressure could be explained by the potential bioactivity of Mg, Ca, Zn, K, and vitamin D (Tarantino et al., 2018), whereas folate was pointed out as the main contributor to the reduction of plasma homocysteine after wholegrain consumption (Priebe & McMonagle, 2016). ...
In recent years, the potential of antiaging interventions that are effective against age-related diseases is gaining increased scientific interest. In this chapter, contribution of wholegrain-based foods can be considered as part of antiaging dietary interventions that are effective against age-related diseases is discussed. Naturally occurring compounds in wholegrain cereals comprised several categories, namely, nondigestible carbohydrates (fiber), phenolic acids, flavonoids, avenanthramides, lignans, alkylresorcinols, carotenoids, phytosterols, and tocols. This chapter highlights the influence of cereal bioactive compounds in preventing aging disorders and augmenting lifespan based on their influence on oxidative stress, inflammation, cellular senescence, and gut microbiota. Moreover, information presented herein encourages research on wholegrain-based strategies and clinical trials to develop a holistic nutrition-oriented antiaging therapy.
... Beyond Wilson's disease, copper homeostasis is disrupted in other chronic liver diseases [1][2][3][4][5]. Indeed, Authors observed that serum copper concentration was significantly higher in cirrhotics than in healthy controls, especially in the oldest [6], with no difference being found in the concentrations of copper between cirrhotics of both genders [7]. ...
Background
Concerning the link between copper excess and the pathogenesis of chronic liver diseases, its retention is reckoned to develop as a complication of cholestasis. Recently, it has been found that cholestatic liver injury involves largely inflammatory cell-mediated liver cell necrosis, with consequent reduced hepatic mass, more than occurring through direct bile acid-induced apoptosis. On the other hand, interference with protein synthesis could be expected to result, ending in an altered ability of the liver to retain copper. Little is known about the association between serum copper and clotting factors in cirrhotics. We aimed at studying a possible relationship between increased levels of copper and an aspect of the haemostatic process in liver cirrhosis patients, assessing an index of protein synthesis (albumin) and parameters of protein synthesis/coagulation/fibrinolysis, such as prothrombin time (PT), antithrombin (AT) III and fibrinogen.
Methods
Records from 85 patients suffering from liver cirrhosis of various aetiology and different severity were retrospectively examined. Serum concentrations of copper were determined by atomic absorption spectrophotometer. An index of protein synthesis, such as albumin and parameters of both synthesis and coagulation/hypercoagulation such as PT %, AT III%, levels of fibrinogen were taken into account to study possible correlations to serum copper. The severity of cirrhosis was evaluated by the Child-Pugh (C-P) classification. The relationship among variables were studied by linear regression.
Results
Copper levels of patients suffering from liver cirrhosis were increased respect to those of controls, 102.7+/-28.7 versus 80.4+/-19.5 mcg/dL, (P = .0009), independently from disease severity, and were positively predicted by PT% (P = 0. 017), fibrinogen (P = 0.007) and AT III% (P = 0.000), at linear regression. Among the previous parameters, to which serum albumin was added, the unique predictor of copper levels was AT III%, at multiple regression (P = 0. 010); AT III% was negatively predicted by the C-P classification (P = 0.000); copper levels, adjusted for C-P classification, were predicted by AT III% (P = 0.020) and fibrinogen concentrations, but not by PT% (P = 0.09).
Conclusion
The copper concentration is reckoned as responsible for production of the hydroxyl radicals. On the basis that oxidants may enhance the activity of the extrinsic coagulation cascade, ultimately leading to thrombin formation, via their combined effects on stimulation of tissue factor activity and inhibition of fibrinolytic pathways, the positive relationship of copper to coagulation/hypercoagulation parameters (mainly AT III) in our research could find a plausible interpretation.
... Oxidizing agents damage deoxyribose and DNA. Likewise, copper bioavailability is a predictor of early atherosclerosis [60]. Phenolics from durum wheat and its processing by-products exhibited protection towards ROS-induced DNA damage and copper-induced oxidation of human low-density lipoprotein (LDL) cholesterol in vitro [1]. ...
A clear gap with respect to the potential biological properties of wheat flavonoids exists in the available literature. This information is crucial for breeding programs aiming to produce new varieties presenting improved health benefits. Accordingly, advanced breeding lines of whole durum wheat were evaluated in this contribution. The highest recovery of phenolics was achieved using aqueous acetone (50:50, v/v), as verified by multi-response optimization, thus showing that phenolics could be largely underestimated by employing an inappropriate extraction. The concentration of derivatives of apigenin, the main phenolics present, ranged from 63.5 to 80.7%, as evaluated by LC–ESI-QTOF-MS. Phenolics from the breeding line 98 exhibited the highest ability in scavenging peroxyl radicals, reducing power as well as in terms of inhibition of pancreatic lipase activity, a key enzyme regulating the absorption of triacylglycerols. In contrast, none of the samples exhibited a significant anti-diabetic potential. Despite their high concentration compared to that of phenolic acids, results of this work do not support a significant antioxidant and pancreatic lipase inhibitory effect of durum wheat flavonoids. Therefore, breeding programs and animal and/or human trials related to the effect of durum wheat flavonoids on oxidative stress and absorption of triacylglycerols are discouraged at this point.
... This is important as we found that ATS is associated with increased copper levels. In obese patients, however, copper levels were inversely associated with intima-media thickness and predicted early ATS [88]. Copper ions may participate in LDL oxidation and are a constituent of antioxidant enzymes including superoxide dismutase and caeruloplasmin [89]. ...
Background
Aberrations in endothelial cells, immune and oxidative pathways are associated with atherosclerosis (ATS) and unstable angina (UA). The role of trace elements, minerals, and the endogenous opioid system (EOS) in UA are less well established.
Methods
We measured lipid, insulin resistance (IR), and immune, trace element (copper and zinc), mineral (magnesium, calcium), EOS (β-endorphin and mu-opioid receptor (MOR)) and antioxidant (vitamin D3) biomarkers in patients with ATS (n = 60) and UA (n = 60) and healthy controls (n = 58).
Results
ATS patients showed increased atherogenic and IR indices, IL-6, IL-10, β-endorphin, copper and magnesium, and lower zinc than healthy controls. Logistic regression showed that UA was significantly discriminated from ATS without UA with an accuracy of 85.5 % using calcium, IL-10, β-endorphin, MOR, triglycerides, IR (all positively), and copper and vitamin D3 (inversely). Neural networks showed that UA was discriminated from ATS without UA with an area under the ROC curve of 0.942 using MOR, β-endorphin, calcium, insulin resistance, vitamin D3 and copper as input variables. We found that 50.0 % of the variance in IR was explained by the regression on copper, IL-10, IL-6 (all positively), and zinc (inversely), while 32.9 % of the variance in the atherogenic index of plasma was explained by copper, IL-10 (both positively), and magnesium (inversely).
Conclusion
UA is not only mediated by insulin resistance, atherogenicity, and immune disorders, but also by aberrations in the endogenous opioid system and trace elements as well as lowered antioxidant levels. Copper appears to play a key role in IR and atherogenicity.
... This is important as we found that ATS is associated with increased copper levels. In obese patients, however, copper levels were inversely associated with intima-media thickness and predicted early ATS [87]. Copper ions may participate in LDL oxidation and are a constituent of antioxidant enzymes including superoxide dismutase and caeruloplasmin [88]. ...
Background: Aberrations in endothelial cells, immune and oxidative pathways are associated with atherosclerosis (ATS) and unstable angina (UA). The role of trace elements, minerals, and the endogenous opioid system (EOS) in UA are less well established. Methods: We measured lipid, insulin resistance (IR), and immune, trace element (copper and zinc), mineral (magnesium, calcium), EOS (β-endorphin and mu-opioid receptor (MOR)) and antioxidant (vitamin D3) biomarkers in patients with ATS (n=60) and UA (n=60) and healthy controls (n=58). Results: ATS patients showed increased atherogenic and IR indices, IL-6, IL-10, β-endorphin, copper and magnesium, and lower zinc than healthy controls. Logistic regression showed that UA was significantly discriminated from ATS without UA with an accuracy of 85.5% using calcium, IL-10, β-endorphin, MOR, triglycerides, IR (all positively), and copper and vitamin D3 (inversely). Neural networks showed that UA was discriminated from ATS without UA with an area under the ROC curve of 0.942 using MOR, β-endorphin, calcium, insulin resistance, vitamin D3 and copper as input variables. We found that 50.0% of the variance in IR was explained by the regression on copper, IL-10, IL-6 (all positively), and zinc (inversely), while 32.9% of the variance in the atherogenic index of plasma was explained by copper, IL-10 (both positively), and magnesium (inversely). Conclusion: UA is not only mediated by insulin resistance, atherogenicity, and immune disorders, but also by aberrations in the endogenous opioid system and trace elements as well as lowered antioxidant levels. Copper appears to play a key role in IR and atherogenicity.
... This is important as we found that ATS is associated with increased copper levels. In obese patients, however, copper levels were inversely associated with intima-media thickness and predicted early ATS [87]. Copper ions may participate in LDL oxidation and are a constituent of antioxidant enzymes including superoxide dismutase and caeruloplasmin [88]. ...
Background. Aberrations in endothelial cells, immune and oxidative pathways are associated with atherosclerosis (ATS) and unstable angina (UA). The role of trace elements, minerals, and the endogenous opioid system (EOS) in UA are less well established.
Methods. We measured lipid, insulin resistance (IR), and immune, trace element (copper and zinc), mineral (magnesium, calcium), EOS (β-endorphin and mu-opioid receptor (MOR)) and antioxidant (vitamin D3) biomarkers in patients with ATS (n=60) and UA (n=60) and healthy controls (n=58).
Results. ATS patients showed increased atherogenic and IR indices, IL-6, IL-10, β-endorphin, copper and magnesium, and lower zinc than healthy controls. Logistic regression showed that UA was significantly discriminated from ATS without UA with an accuracy of 85.5% using calcium, IL-10, β-endorphin, MOR, triglycerides, IR (all positively), and copper and vitamin D3 (inversely). Neural networks showed that UA was discriminated from ATS without UA with an area under the ROC curve of 0.942 using MOR, β-endorphin, calcium, insulin resistance, vitamin D3 and copper as input variables. We found that 50.0% of the variance in IR was explained by the regression on copper, IL-10, IL-6 (all positively), and zinc (inversely), while 32.9% of the variance in the atherogenic index of plasma was explained by copper, IL-10 (both positively), and magnesium (inversely).
Conclusion. UA is not only mediated by insulin resistance, atherogenicity, and immune disorders, but also by aberrations in the endogenous opioid system and trace elements as well as lowered antioxidant levels. Copper appears to play a key role in IR and atherogenicity.
... Secondly, it was reported that copper may play a key role in NAFLD pathogenesis. A tight link between copper homeostasis and lipid metabolism has been well recognized (Feldman et al., 2015;Tarantino et al., 2018). Resent study found that adipocyte-specific Atp7a, a P-type ATPase that transports copper across cell membranes, knockout mice present hepatic steatosis and upregulated peroxisome proliferator activated receptor g (PPARg) in gonadal white adipose tissue (Tao et al., 2019). ...
Psoralea corylifolia L. (PC) is a traditional Chinese herb used to treat yang deficiency of the spleen and kidney in pediatric disease. Our previous studies have found that PC can alleviate the liver oxidative stress of juvenile mice with nonalcoholic steatohepatitis (NASH), and its mechanism is related to the inhibition of the protein kinase C-α (PKC-α)/nicotinamide-adenine dinucleotide phosphate oxidase (NOX) signaling pathway. The aim of this study was to confirm the aforementioned drug target in vitro and to conduct preliminary screening for some effective compounds of PC on the treatment of NASH. A primary hepatocyte model of non alcoholic fatty liver disease was established by palmitic acid. The existence of Psoralen, Isopsoralen, Neobavaisoflavone, Isobavachalcone, and Bakuchiol were identified by ultra-performance liquid chromatography. Then, five PC compounds were administered. Intracellular triglyceride and total cholesterol content, the cell supernatant alanine aminotransferase and aspartate aminotransferase, and hepatocellular superoxide anion were examined. The changes of PKC-α/NOX signaling pathways in hepatocytes were also determined. Furthermore, PKC-α activator phorbol 12-myristate 13-acetate was administered for 4 h before Psoralen intervention was conducted again to detect the changes of PKC-α/NOX signaling pathways. Our data demonstrated that Psoralen, Isopsoralen, and Isobavachalcone decreased intracellular content of triglyceride while all five PC compounds improved hepatocellular total cholesterol accumulation and hepatocyte damage in palmitic acid-induced primary hepatocyte model of non alcoholic fatty liver disease. All five PC compounds could also reduce hepatocytic superoxide anion levels, nicotinamide-adenine dinucleotide phosphate/reduced nicotinamide-adenine dinucleotide phosphate ratio, NOX activity as well as p47phox protein expression and PKCα activation in hepatocytes. Psoralen exhibited the best efficacy but the effectiveness was lost when pre-stimulated by phorbol 12-myristate 13-acetate. The results suggest that Psoralen, Isopsoralen, and Isobavachalcone could improve hepatocyte steatosis; five PC compounds could ameliorate hepatocyte injury, relieve oxidative stress, and downregulate the PKC-α/NOX signaling pathway of hepatocytes. In addition, Psoralen exhibits the best efficacy and a prospective PKC-α inhibitor pharmaceutical activity.
... 101 Copper identified as a key player in several metabolic derangements. 102 Chelating agents inhibit metal-catalyzed production of reactive oxygen species, thereby inhibiting chemical damage to proteins and subsequent pro-inflammatory cascades. Using copper and iron chelator is a promising treatment strategy to prevent/reverse organ damage in diabetes, heart failure, and neurodegenerative diseases. ...
Type 2 diabetes (T2DM) is a chronic metabolic disorder. Impaired insulin secretion, enhanced hepatic glucose production, and suppressed peripheral glucose use are the main defects responsible for developing the disease. Besides, the pathophysiology of T2DM also includes enhanced glucagon secretion, decreased incretin secretion, increased renal glucose reabsorption, and adipocyte, and brain insulin resistance. The increasing prevalence of T2DM in the world beseeches an urgent need for better treatment options. The antidiabetic drugs focus on control of blood glucose concentration, but the future treatment goal is to delay disease progression and treatment failure, which causes poorer glycemic regulation. Recent treatment approaches target on several novel pathophysiological defects present in T2DM. Some of the promising novel targets being under clinical development include those that increase insulin sensitization (antagonists of glucocorticoids receptor), decreasing hepatic glucose production (glucagon receptor antagonist, inhibitors of glycogen phosphorylase and fructose-1,6-biphosphatase). This review summarizes studies that are available on novel targets being studied to treat T2DM with an emphasis on the small molecule drug design. The experience gathered from earlier studies and knowledge of T2DM pathways can guide the anti-diabetic drug development toward the discovery of drugs essential to treat T2DM.
... Trace metals including iron, zinc and copper are essential for many cellular functions and for optimal adaptive and innate immune responses (151). Among these three metals, iron and copper exert an important influence on the genesis of NAFLD (152)(153)(154)(155). Adults, but not children, with NAFLD manifest increased circulating concentrations of ferritin; however, both age groups exhibit increased transferrin saturation (153,154). ...
Obesity is a prevalent predisposing factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the developed world. NAFLD spectrum of disease involves progression from steatosis (NAFL), to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Despite clinical and public health significance, current FDA approved therapies for NAFLD are lacking in part due to insufficient understanding of pathogenic mechanisms driving disease progression. The etiology of NAFLD is multifactorial. The induction of both systemic and tissue inflammation consequential of skewed immune cell metabolic state, polarization, tissue recruitment, and activation are central to NAFLD progression. Here, we review the current understanding of the above stated cellular and molecular processes that govern macrophage contribution to NAFLD pathogenesis and how adipose tissue and liver crosstalk modulates macrophage function. Notably, the manipulation of such events may lead to the development of new therapies for NAFLD.
... [48] Furthermore, hepatic copper concentrations was found to vary inversely according to iron status, [49] and impaired bioavailability of copper has been proved to play an important role in the pathogenesis of NAFLD. [50] On the one hand, low copper bioavailability can attribute to lipid metabolism and that it may therefore be related to the development of NAFLD. [51] On the other hand, systemic copper deficiency could also lead to changes in mitochondrial morphology owing to its effects on respiratory chain physiology and function, which has been implicated in the pathogenesis of NAFLD. ...
The aim was to test the association between dietary iron intake and the prevalence of nonalcoholic fatty liver disease (NAFLD) in a large sample of middle-aged and elderly Chinese population.
The data included in this analysis were collected from a population-based cross-sectional study, that is, the Xiangya Hospital Health Management Center Study. Dietary iron intake was assessed using a validated semiquantitative food frequency questionnaire. The relationship between dietary iron intake and the prevalence of NAFLD was examined using logistic and spline regressions.
A cross-sectional study including 5445 subjects was conducted. The prevalence of NAFLD was 36.9%. Compared with the lowest quintile, the energy-adjusted odds ratios (ORs) of NAFLD were 1.33 (95% confidence interval [CI]: 1.07–1.64), 1.80 (95% CI: 1.41–2.29) and 2.11 (95% CI: 1.60–2.80) in the 3rd, 4th, and 5th quintile of iron intake, respectively (P-value for trend <.001). In addition, dietary iron intake was positively associated with the OR of NAFLD in a dose–response relationship manner (test for trend P < .001). However, after stratifying the data by gender, such association only remained in the male, but not in the female population. With adjustment of additional potential confounders, the results did not change materially.
Subjects with higher dietary iron intake were subject to a higher prevalence of NAFLD in a dose–response relationship manner. However, such association probably only exists in males, but not in females.
... Environmental factors, including sun exposure to vitamin D and infections, are considered risks of MS after the age of 15 [22]. Several studies showed the infectious etiology of MS in adults and children [ Given that the altered homeostasis of metals is associated with the initiation and progression of various diseases such as cardiovascular diseases and neurodegenerative disorders [24]. Recent reports indicated that the physiology of redox metals that produce oxidative stress, which in turn leads to cascades of immunomodulatory alteration of neurons in MS and amyotrophic lateral sclerosis [25]. ...
Multiple sclerosis (MS), an autoimmune disorder associated with spinal cord and brain,
chiefly affects the white matter. Regarding the complexity as well as heterogenic etiology of this
disease, the treatment of MS has been a challenging issue up to now. Researchers are working to
develop new therapeutic strategies and drugs as complementary therapies. MS diagnosis significantly
depends on the findings of Magnetic resonance imaging (MRI) examination. In this imaging technique,
gadolinium is used as a contrast agent to reveal active plaques intending to destroy the bloodbrain
barrier. It also detects plaques that are not correlated with the neurological symptoms. It has
been attempted to determine biomarkers related to different dimensions of MS in various organizational
hierarchy levels of the human anatomy (i.e., cells, proteins, RNA, and DNA). These biomarkers
are appropriate diagnostic tools for MS diagnosis. In this review, we summarized the application
of MRI and biochemical biomarkers to monitor MS patients. Moreover, we highlighted the joint application
of MRI and biomarkers for the diagnosis of MS subjects.
... Increasing evidence highlight the association between copper homeostasis and lipid metabolism [37], with altered copper bioavailabity shown to predict early atherosclerosis, suggesting that copper bioavailability is a potential biomarker for future cardiovascular risk assessment in obese patients with hepatic steatosis [38]. Copper is an essential element for most living organisms and plays a vital role in numerous cellular and physiological functions [39,40]. ...
Obesity is a significant contributor to increased morbidity and premature mortality due to increasing the risk of many chronic metabolic diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle modifications such as energy restriction and increased physical activity are highly effective first-line treatment strategies used in the management of obesity. However, adherence to these behavioral changes is poor, with an increased reliance on synthetic drugs, which unfortunately are plagued by adverse effects. The identification of new and safer anti-obesity agents is thus of significant interest. In recent years, plants and their phenolic constituents have attracted increased attention due to their health-promoting properties. Amongst these, Cyclopia, an endemic South African plant commonly consumed as a herbal tea (honeybush), has been shown to possess modulating properties against oxidative stress, hyperglycemia, and obesity. Likewise, several studies have reported that some of the major phenolic compounds present in Cyclopia spp. exhibit anti-obesity effects, particularly by targeting adipose tissue. These phenolic compounds belong to the xanthone, flavonoid and benzophenone classes. The aim of this review is to assess the potential of Cyclopia extracts as an anti-obesity nutraceutical as underpinned by in vitro and in vivo studies and the underlying cellular mechanisms and biological pathways regulated by their phenolic compounds.
... Finally, another systematic review and meta-analysis illustrated that while no reduction in liver chemistries were observed among patients with NAFLD, a low carbohydrate diet decreased intrahepatic lipid content by 11.53% (95% CI: −18.10, −4.96) (55). Furthermore, a decrease in copper bioavailability has been demonstrated to contribute to atherosclerosis among NAFLD patients (56). ...
The progression of liver disease is portrayed by several common, overarching signs and symptoms. Classically, these include findings such as spider angiomata, jaundice, palmar erythema, and as cirrhosis decompensates, ascites, variceal hemorrhage (VH), hepatic encephalopathy (HE), and hepatocellular carcinoma (HCC). Aside from these universal hallmarks among cirrhotics, patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) harbor their own distinct systemic associations and manifestations. NAFLD is tightly linked to metabolic syndrome, which appears to be a driving force for a multitude of comorbidities, such as insulin resistance, cardiovascular disease, chronic kidney disease (CKD), obstructive sleep apnea (OSA), as well as increased malignancy risk. ALD also maintains a variety of comorbidities congruent with systemic effects of chronic alcohol use. These findings are highlighted by cardiovascular conditions, neuronal damage, myopathy, nutritional deficiencies, chronic pancreatitis, in addition to increased malignancy risk. While a general, guideline-driven management for all cirrhotic patients remains imperative for minimizing risk of complications, a tailored treatment strategy is useful for patients with NAFLD and ALD who entertain their own constellation of unique systemic manifestations.
... Confounding factors, comorbidities, or simple blood parameters can significantly impact the progression or overall outcome of NASH. This was recently documented in a cross-sectional study in which 100 obese patients suffering from hepatic steatosis were analyzed for the occurrence of atherosclerosis [99]. Interestingly, the authors found that a lowered copper bioavailability is linked to atherosclerosis, which is the main complication of NAFLD. ...
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis.
... It is noteworthy that copper bioavailability is impaired in patients with obesity-related nonalcoholic fatty liver disease and suffering from atherosclerosis (main mechanism of acute and chronic cardiac events) [71]. ...
Thymosin beta-4 (Tβ4) is known as a major pleiotropic actin-sequestering protein that is involved in tumorigenesis. Tβ4 is a water-soluble protein that has different promising clinical applications in the remodeling and ulcerated tissues repair following myocardial infarction, stroke, plasticity and neurovascular remodeling of the peripheral nervous system (PNS) and the central nervous system (CNS). On the other hand, similar effects have been observed for Tβ4 in other kinds of tissues, including cardiac muscle tissue. In recent reports, due to its activation of resident epicardial progenitor cells and modulation of inflammatory-caused injuries, Tβ4 has been suggested as a promoter of the survival of cardiomyocytes. Furthermore, Tβ4 may in skeletal muscle and different organs act in association/synergism with numerous other tissue repair stimulating factors, including melatonin and C-fiber-derived peptides. For these reasons, the present review highlights the promising role of Tβ4 in cardiac healing.
... However, the potential roles for insufficient copper in the pathogenesis of liver disease, namely the Wilson's disease, requires further study of the interaction of melatonin and copper in the reduction of free radicals [40]. Moreover, the research results also show that the change in the bioavailability of copper predicts early atherosclerosis as a major risk of cardiovascular disease, in obese patients with hepatic steatosis [41]. ...
Background and objectives: toxic liver injury results in nitrooxidative stress. Melatonin is a potent free radical scavenger, an inducible nitric oxide synthase (iNOS) inhibitor and an activator of antioxidant enzymes. The aim of this study was to investigate the hepatoprotective effect of exogenous melatonin on animals with acute toxic hepatitis. Material and methods: 36 healthy Sprague-Dawley male rats were split into three equal groups and given carbon tetrachloride (CCl4), 2 g/kg (CCl4 group) or the same dose of CCl4 and melatonin, 10 mg/kg (CCl4/melatonin group) or saline (control group). The effect of melatonin on prooxidant and antioxidant system indexes, NO and NOS levels in serum and liver, data of mitochondrial chain functions and cytolysis in liver were evaluated in all three groups. Results: melatonin significantly decreased activities of AST, ALT, ceruloplasmine and thiobarbituric acid reactive substance (TBARS) in serum. Catalase activity was lowered in serum but not in the liver. Hepatic TBARS, lipid hydroperoxides and glutathione concentrations were decreased, while superoxide dismutase, mitochondrial cytochrome oxidase and succinate dehydrogenase activities increased. Melatonin inhibited synthesis of stable NO metabolites in serum: NO2-by 37.9%; NO3-by 29.2%. There was no significant difference in content NO2-in the liver, but concentration of NO3-increased by 32.6%. Melatonin significantly reduced iNOS concentrations both in serum (59.7%) and liver (57.8%) but did not affect endothelial isoform enzyme activities neither in serum, nor in liver. The histopathological liver lesions observed in the CCl4/melatonin group were less severe than those seen in the CCl4 group. Conclusions: we demonstrated an ameliorating effect of melatonin on prooxidants and antioxidants, NO-NOS systems balance, mitochondrial function and histopathological lesions in the liver in rats with CCl4-induced hepatitis.
... A mineral element, such as copper is important in the regulation of oxidative free radicals and its deficiency increases the susceptibility to lipoprotein peroxidation and increase in plasma cholesterol concentrations [22,23]. Occurrence of non-alcoholic fatty liver diseases (NAFLD) has been linked to an alteration in the homeostasis of metals like copper [24]. This occurs in individuals with low copper levels as a consequence of copper deficient diets and sedentary life style [25]. ...
Dietary deficiencies have become significant in public health challenge globally. This is attributed in part to the pitiable quality of customary diets and the absence of variety in meals. Nutrition and health are closely related, and micronutrient deficiencies are one of the major culprits responsible for the positive correlation between diet and various diseases. Green leafy vegetables are important sources of micronutrients in most African rural communities where they have been used as an accompaniment for staple cereals and root-based diets for many years. Green leafy vegetables from Celosia species are good examples that could contribute to the prevention and management of micronutrient deficiencies and also provide food security. The main objective of this review is to highlight and bring to fore, the suitability of Celosia vegetables in preventing malnutrition and chronic diseases. Various electronic search databases including PubMed, ISI, Web of Science and CNKI were used to review existing literatures. Findings showed that Celosia species are good sources of nutrients that could prevent dietary deficiencies and chronic diseases. Also, the possible use of Celosia spp. in the development of functional foods has the potential to reduce malnutrition and foster complementary plans for the prevention and management of diseases. Therefore, further studies on formulations of food products using vegetables from Celosia species could contribute to the prevention and management of micronutrient deficiencies, chronic diseases and also provide food security.
Peripheral arterial disease (PAD) is becoming more prevalent in the aging developed world and can have significant functional impacts on patients. There is a recent recognition that environmental toxicants such as circulating metals and metalloids may contribute to the pathogenesis of atherosclerotic disease, but the mechanisms are complex. While the broad toxic biologic effects of metals in human systems have been extensively reviewed, the role of non-essential exposure and essential metal aberrancy in PAD specifically is less frequently discussed. This review of the literature describes current scientific knowledge regarding the individual roles several major metals and metalloids play in atherogenesis and highlights areas where a dearth of data exist. The roles of lead (Pb), arsenic (As), cadmium (Cd), iron (Fe), copper (Cu), selenium (Se) are included. Contemporary outcomes of therapeutic trials aimed at chelation therapy of circulating metals to impact cardiovascular outcomes are also discussed. This review highlights the supported notion of differential metal presence within peripheral plaques themselves, although distinguishing their roles within these plaques requires further illumination.
Solute carrier (SLC) family transporters are crucial transmembrane proteins responsible for transporting various molecules, including amino acids, electrolytes, fatty acids, and nucleotides. To date, more than fifty SLC transporter subfamilies have been identified, many of which are linked to the progression of hepatic steatosis and fibrosis. These conditions are often caused by factors such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which are major contributors to the global liver disease burden. The activity of SLC members regulates the transport of substrates across biological membranes, playing key roles in lipid synthesis and metabolism, mitochondrial function, and ferroptosis. These processes, in turn, influence the function of hepatocytes, hepatic stellate cells, and macrophages, thereby contributing to the development of hepatic steatosis and fibrosis. Additionally, some SLC transporters are involved in drug transport, acting as critical regulators of drug-induced hepatic steatosis. Beyond substrate transport, certain SLC members also exhibit additional functions. Given the pivotal role of the SLC family in hepatic steatosis and fibrosis, this review aimed to summarize the molecular mechanisms through which SLC transporters influence these conditions.
Copper (Cu) is a necessary micro-element and plays important roles in many biochemical processes. However, excessive Cu intake can lead to multi-organ toxicity, especially in the spleen. To gain further insights into the specific mechanisms of splenic toxicity associated with Cu-induced metabolic disorders, 192 one-day-old chickens were selected and randomly divided into four groups for this study. The broilers were fed with diets containing Cu at final concentrations of 11, 110, 220 and 330 mg/kg for 49 days. The results showed that high dietary Cu caused nuclear shrinkage and mitochondrial vacuolization in the spleen and induced splenic injury through regulating the glutathione metabolism, pentose and gluconate interconversion, tryptophan metabolism and glycerophosphatidylcholine metabolism pathways. Moreover, excess Cu could disorder the mitochondrial dynamics via up-regulating the levels of Drp1, Parkin PINK1, and Dynein, and down-regulating the levels of Mfn1, Mfn2 and OPA1. Cu treatment increased the levels of LC3A, LC3B, mTOR, Beclin1, and ATG5 and decreased the p62 level to promote autophagy of splenocytes. Meanwhile, a high dose of Cu promoted splenocyte apoptosis by increasing the levels of p53, BAK-1, Bax, Cyt C and Caspase-3 and decreasing the level of Bcl-2. These results demonstrated that high dietary Cu could cause autophagy and apoptosis via inducing metabolic disturbances and disordering mitochondrial dynamics in the spleen of broiler chicken.
Background/Objectives: A diet enriched with copper nanoparticles (CuNPs) exhibits a wide range of effects on liver metabolism, both positive and negative. Dietary fibers are the key components that may affect the absorption of minerals, including copper, and change their impact on organisms. Methods: Therefore, this study investigated whether and how supplementation with different sources of dietary fiber (cellulose, pectin, inulin, and psyllium) affects the function of CuNPs in the liver of male Wistar rats. Results: The results showed that CuNPs at different doses had varying effects on lipid metabolism and inflammation in the liver. Specifically, higher doses of CuNPs were associated with increased lipid accumulation and the activation of pro-inflammatory mechanisms. However, combining CuNPs with dietary fibers, such as psyllium and inulin, was beneficial in mitigating the effects of the examined nanoparticles, leading to reduced fat, cholesterol, and triglycerides in the liver. Combining psyllium with CuNPs showed the most substantial effect on liver metabolism and inflammation parameters. Furthermore, hepatic histology analyses showed that adding psyllium to the diet with CuNPs reduces changes associated with fat accumulation and mononuclear cell infiltration. The observed beneficial changes in the liver may have been related to a reduction in the gene expression level of sterol regulatory element-binding protein 1 and peroxisome proliferator-activated receptor gamma and cyclooxygenase-2. Conclusions: In conclusion, enriching the diet with dietary fibers such as psyllium can regulate the action of CuNPs, thereby improving lipid metabolism and reducing inflammation in the liver.
Aims
To explore the associations between cuprotosis‐related genes (CRGs) across different stages of liver disease in metabolic dysfunction‐associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC).
Materials and Methods
We analysed several bulk RNA sequencing datasets from patients with MAFLD ( n = 331) and MAFLD‐related HCC ( n = 271) and two MAFLD single‐cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients ( n = 656) used for a genome‐wide association study (GWAS).
Results
GLS , GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD‐related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction‐associated fatty liver to metabolic‐associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD.
Conclusions
GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T‐cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.
Non‐alcoholic fatty liver disease (NAFLD), a metabolic‐associated fatty liver disease, has become the most common chronic liver disease worldwide. Recently, the discovery of cuproptosis, a newly identified mode of cell death, further highlighted the importance of copper in maintaining metabolic homeostasis. An increasing number of studies have confirmed that liver copper metabolism is closely related to the pathogenesis of NAFLD. However, the relationship between NAFLD and copper metabolism, especially cuproptosis, remains unclear. In this review, we aim to summarize the current understanding of copper metabolism and its dysregulation, particularly the role of copper metabolism dysregulation in the pathogenesis of NAFLD. More importantly, this review emphasizes potential gene‐targeted therapeutic strategies, challenges and the future of cuproptosis‐related genes in the treatment of NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD.
Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.
There is an increasing evidence pointing to a possible correlation between AMI and copper levels. Serum copper levels serve as a valuable biomarker for assessing the body's copper status. Objective: To find the changes in serum copper level in patients with Acute Myocardial Infarction (AMI). Methods: This observational study was conducted in District Headquarter Hospital, Nowshera in duration of two years. A total of 240 patients were recruited in this study. Upon admission, demographic information, medical history, and clinical characteristics were collected. Blood samples were obtained for measurement of serum copper levels using established laboratory methods. All data were analyzed through SPSS version 29.0. Results: Among total, 65% males and 35% females and the prevalence of cardiovascular risk factors was notable, with 70% of patients having hypertension, 40% with diabetes mellitus, 60% with dyslipidemia, and 45% identified as smokers. Baseline serum copper levels averaged 110 ± 5.2 µg/dL, within 24 hours of admission, the peak serum copper level significantly increased to 125 ± 18.6 µg/dL. Subsequently, levels decreased gradually over the following days, with mean values of 120 ± 17.1 µg/dL on Day 2, 115 ± 16.4 µg/dL on Day 3, 112 ± 15.9 µg/dL on Day 4, and returning to baseline levels by Day 5, 110 ± 15.2 µg/dL. Conclusions: Serum copper levels exhibit significant changes during the acute phase of AMI, with a peak observed within 24 hours of admission. While patients with anterior infractions showed higher peak copper levels, no significant associations were found between copper levels and traditional cardiovascular risk factors or inflammatory markers
Background Non-alcoholic fatty liver disease (NAFLD) is a widely prevalent hepatic disorder resulting in the high risk of adverse prognosis, and the presence of which has been considered as a...
Background
: Zinc deficiency is common in patients with non-alcoholic fatty liver disease (NAFLD) and evidence indicates the role of zinc as an antioxidant and improvement in insulin resistance in obesity and type 2 diabetes. The aim of this study was to investigate the effects of zinc supplementation on mental health among overweight/obese patients with NAFLD.
Methods
: Fifty- six overweight/obese subjects with confirmed non-alcoholic fatty liver disease (NAFLD) were randomly allocated to treatment (30 mg/day supplement) or placebo groups under a calorie restricted diet for 12 weeks. Mental health was assessed using a valid 21-item questionnaire, the Depression, Anxiety, and Stress Scale (DASS-21). Anthropometric measurements, food assessment, and mental health were assessed at the first, 6th, and 12th weeks. Serum zinc was assessed at the beginning and end of the intervention.
Results
: A total of 50 participants completed the study. Serum zinc deficiency was significantly compensated in the treatment group (P<0.05). Although the DASS-21 depression, anxiety, and stress scores decreased significantly during the intervention, after adjusting for confounder factors, no significant differences were seen between the two groups. After 12 weeks, only waist circumference decreased significantly in the treatment group compared to the placebo group (P<0.05).
Conclusions
: The study showed daily intake of 30 mg of zinc elemental improves zinc deficiency and waist circumference in patients with NAFLD. However, further clinical trial studies with a longer duration, dose-dependent and considering gender and severity of mood disorders are needed to clarify the effect of zinc supplementation on depression, anxiety, and stress in overweight/obese patients with NAFLD [IR.MUI.RESEARCH.REC.1399.071].
Gluten triggers celiac disease (CD) and type I diabetes in genetically predisposed population of human leukocyte antigen DQ2/DQ8+ and associates with disorders such as schizophrenia and autism. Application of a strict gluten-free diet is the only well-established treatment for patients with CD, whereas the treatment for patients with celiac type I diabetes may be depend on the timing and frequency of the diet. The application of a gluten-free diet in patients with CD may contribute to the development of metabolic syndrome and nonalcoholic fatty liver disease and may also lead to a high glycemic index, low fiber diet and micronutrient deficiencies. The alteration of copper bioavailability (deficient, excess or aberrant coordination) may contribute to the onset and progress of related pathologies. Therefore, nutrient intake of patients on a gluten-free diet should be the focus of future researches. Other gluten-based therapies have been rising with interest such as enzymatic pretreatment of gluten, oral enzyme supplements to digest dietary gluten, gluten removal by breeding wheat varieties with reduced or deleted gluten toxicity, the development of polymeric binders to suppress gluten induced pathology.
Nonalcoholic fatty liver disease (NAFLD) is a considerable challenge to public health across the globe. Whole grain is highly recommended as an inseparable part of a healthy diet and has been proposed as an effective way to manage NAFLD. The objective in this study was to evaluate the effects of whole grain consumption on hepatic steatosis and liver enzymes as primary outcomes in patients with NAFLD. Over the 12 weeks of this open-label, randomized controlled clinical trial, 112 patients [mean age: 43± 8.7 y; body mass index (BMI) (kg/m ² ): 32.2 ± 4.3] were randomly assigned to two groups to receive dietary advice; either to obtain at least half of their cereal servings each day from whole-grain foods or from usual cereals. By the end of the study, the grades of NAFLD showed a significant decrease in the intervention group (P < 0.001). In addition, a significant reduction in serum concentration of alanine aminotransferase (P < 0.001), aspartate aminotransferase (P < 0.001), γ-glutamyltransferase (P = 0.009), systolic blood pressure ( P = 0.004) and diastolic blood pressure ( P = 0.008) were observed in the intervention group compared to the control group. After adjusting, however, no significant differences were found between the two groups in terms of lipid profile, glycemic status, and anthropometric measurements. Overall, our study demonstrated that consumption of whole grains for 12 weeks had beneficial effects on hepatic steatosis and liver enzymes concentrations in patients with NAFLD.
Background: N-acetyl-cysteine (NAC) has shown widespread utility in different psychiatric disorders, including a beneficial role in schizophrenic patients. Although the replenishment of glutathione and the antioxidant activity of NAC have been suggested as the mechanisms that improve such a wide range of disorders, none seems to be sufficiently specific to explain these intriguing effects. A sensitive cysteine proteome is emerging as a functional and structural network of interconnected sensitive cysteine-containing proteins (SCCPs) that together with reactive species and the cysteine/glutathione cycles can regulate the bioenergetic metabolism, the redox homeostasis and the cellular growth, differentiation and survival, acting through different pathways that are regulated by the same thiol radical in cysteine residues.
Objective: Since this sensitive cysteine network has been implicated in the pathogenesis of Parkinson’s and Alzheimer ́s diseases. I have reviewed if the proteins that play a role in schizophrenia can be classified as SCCPs.
Results: The results show that the principal proteins playing a role in schizophrenia can be classified as SCCPs, suggesting that the sensitive cysteine proteome (cysteinet) is defective in this type of psychosis.
Conclusion: The present review proposes that there is a deregulation of the sensitive cysteine proteome in schizophrenia as the consequence of a functional imbalance among different SCCPs, which play different functions in neurons and glial cells. In this context, the role of NAC to restore and prevent schizophrenic disorders is discussed.
Background:
Allyl isothiocyanate (AITC), a classic anti-inflammatory and antitumorigenic agent, was recently identified as a potential treatment for obesity and insulin resistance. However, little is known about its direct impact on the liver.
Aim:
To investigate the effect and underlying mechanism of AITC in nonalcoholic fatty liver disease (commonly referred to as NAFLD).
Methods:
To establish a mouse and cellular model of NAFLD, C57BL/6 mice were fed a high fat diet (HFD) for 8 wk, and AML-12 cells were treated with 200 μM palmitate acid for 24 h. For AITC treatment, mice were administered AITC (100 mg/kg/d) orally and AML-12 cells were treated with AITC (20 μmol/L).
Results:
AITC significantly ameliorated HFD-induced weight gain, hepatic lipid accumulation and inflammation in vivo. Furthermore, serum alanine aminotransferase and aspartate aminotransferase levels were markedly reduced in AITC-treated mice. Mechanistically, AITC significantly downregulated the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and its lipogenesis target genes and upregulated the levels of proteins involved in fatty acid β-oxidation, as well as the upstream mediators Sirtuin 1 (Sirt1) and AMP-activated protein kinase α (AMPKα), in the livers of HFD-fed mice. AITC also attenuated the nuclear factor kappa B (NF-κB) signaling pathway. Consistently, AITC relieved palmitate acid-induced lipid accumulation and inflammation in AML-12 cells in vitro through the Sirt1/AMPK and NF-κB signaling pathways. Importantly, further studies showed that the curative effect of AITC on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPKα in AML-12 cells.
Conclusion:
AITC significantly ameliorates hepatic steatosis and inflammation by activating the Sirt1/AMPK pathway and inhibiting the NF-κB pathway. Therefore, AITC is a potential therapeutic agent for NAFLD.
High-fat diet (HFD)-induced obese-insulin resistance negatively affects bone via gut microbiota dysbiosis-triggered systemic inflammation. The biotic treatment can improve metabolic status in HFD-fed rats. However, the microarchitectural analysis by bone histomorphometry of the tibia have not been determined. Forty-eight male Wistar rats were fed with normal diet or HFD for 24 weeks. At week13, rats were received either a vehicle, Lactobacillus paracasei HII01, xylooligosaccharides, or synbiotics. Blood analyses and tibial histomorphometry were performed. We found that L. paracasei HII01, xylooligosaccharides, and synbiotics improved obese-insulin resistance and systemic inflammation in HFD-fed rats. These biotics equally increased bone volume fraction and trabecular thickness, reduced osteoclast surface and active erosion surface, increased the double labeled surface, mineralizing surface, mineral apposition rate and bone formation rate of HFD-fed rats. In conclusion, these biotic therapies exerted an enhancement of bone microarchitecture in HFD-fed rats possibly by mitigating osteoclast-mediated bone resorption and promoting osteoblast-induced bone formation.
Fructose as a daily sweetener is widely recognized as a risk catalyst for non-alcoholic fatty liver disease (NAFLD). The aim of current study is to evaluate the effects and molecular mechanism by which polyphenol-rich loquat fruit extract (LFP) prevents NAFLD in mice fed 30% fructose water (HF) for 8 weeks. Administration of LFP to HF-fed mice mitigated abnormal body weight, disordered lipid metabolism, oxidative stress and inflammation through a mechanism regulated by the AKT, ChREBP/SREBP-1c, Nrf2 and TLR4/MyD88/TRIF pathways. LFP caused a significant decrease in the endotoxin content (16.67-12.7 EU/mL) in the liver of HF-fed mice. LFP not only improved HF-induced breakage of the intestinal barrier via interacting with tight junction proteins (ZO-1, occludin), mucin and immunoreaction in the colon but also maintained normal colonic Firmicutes/Bacteroidetes ratios and the relative abundance of Veillonella in HF-fed mice. Our results suggest that LFP may serve as a nutritional agent for protecting liver in HF-fed mice.
Atherosclerotic disease is the most important cause of mortality in the world. Oxidation is an important pathway in the pathogenesis of coronary artery disease (CAD) through oxidation of low-density lipoprotein (LDL) and free radical formation. Copper (Cu) is an essential micronutrient for enzymes that catalyse LDL oxidation reactions. Therefore, an evaluation of Cu in the atherosclerotic disease is important.
In this study, 334 subjects without recent cardiac event and history of collagen vascular or infectious disease were investigated. All patients divided into four groups to evaluate severity of CAD according to Syntax scoring system. All groups were matched in cardiovascular risk factors.
The serum level of Cu was significantly higher in total atherosclerotic groups than normal group (P value = 0.001) and significantly increased with severity of atherosclerosis.
The finding indicated that the serum level of Cu is higher in atherosclerotic patients and it increases with severity of atherosclerosis. Therefore, it may be possible that the basic relationship exist between serum Cu level and atherosclerosis and an association between Cu level and severity of atherosclerosis.
Nonalcoholic fatty liver disease (NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis (increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific life-style modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.
Copper (Cu) is an essential microelement found in all living organisms with the unique ability to adopt two different redox states-in the oxidized (Cu(2+)) and reduced (Cu(+)). It is required for survival and serves as an important catalytic cofactor in redox chemistry for proteins that carry out fundamental biological functions, important in growth and development. The deficit of copper can result in impaired energy production, abnormal glucose and cholesterol metabolism, increased oxidative damage, increased tissue iron (Fe) accrual, altered structure and function of circulating blood and immune cells, abnormal neuropeptides synthesis and processing, aberrant cardiac electrophysiology, impaired myocardial contractility, and persistent effects on the neurobehavioral and the immune system. Increased copper level has been found in several disorders like e.g.: Wilson's disease or Menke's disease. New findings with the great potential for impact in medicine include the use of copper-lowering therapy for antiangiogenesis, antifibrotic and anti-inflammatory purposes. The role of copper in formation of amyloid plaques in Alzheimer's disease, and successful treatment of this disorder in rodent model by copper chelating are also of interest. In this work we will try to describe essential aspects of copper in chosen diseases. We will represent the evidence available on adverse effect derived from copper deficiency and copper excess. We will try to review also the copper biomarkers (chosen enzymes) that help reflect the level of copper in the body.
Cigarette smoking is a major risk factor for cardiovascular disease (CVD) and the leading avoidable cause of death worldwide. Exposure to secondhand smoke (SHS) increases the risk of CVD among non-smokers. Smoking cessation benefits all smokers, regardless of age or amount smoked. The excess risk of CVD is rapidly reversible, and stopping smoking after a myocardial infarction reduces an individual's risk of CVD mortality by 36% over 2 years. Smoking cessation is a key component of primary and secondary CVD prevention strategies, but tobacco use often receives less attention from cardiologists than other risk factors, despite the availability of proven treatments that improve smoking cessation rates. Both psychosocial counselling and pharmacotherapy are effective methods to help smokers quit, but they are most effective when used together. The first-line medications licensed to aid smoking cessation, nicotine replacement therapy, bupropion and varenicline, are effective in and appropriate for patients with CVD. An evidence-based approach for physicians is to routinely ask all patients about smoking status and SHS exposure, advise all smokers to quit and all patients to adopt smoke-free policies for their home and car, and offer all smokers in the office or hospital brief counselling, smoking cessation pharmacotherapy, and referral to local programmes where psychosocial support can be sustained in person or by telephone. Like other chronic diseases, tobacco use requires a long-term management strategy. It deserves to be managed as intensively as other CVD risk factors.
Background
Defective copper regulation is implicated as a causative mechanism of organ damage in diabetes. Treatment with trientine, a divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it also ameliorates left-ventricular (LV) hypertrophy. However, direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking.
Methods
To determine whether trientine treatment could improve in vivo outcome, we measured cardiac function in groups of trientine-treated diabetic (TETA-DIA), non-drug-treated diabetic (DIA) and sham-treated control (SHAM) rats, by using in vivo high-field cardiac magnetic-resonance imaging (cMRI) and an ex vivo isolated-perfused working heart method. Forty age-matched animals underwent a cMRI scan after which 12 were randomized to the SHAM group and 28 underwent streptozotocin-injection; of these, 25 developed stable diabetes, and 12 were then randomized to receive no treatment for 16 weeks (DIA) and the other 13 to undergo 8-weeks’ untreated diabetes followed by 8-weeks’ drug treatment (TETA-DIA). Animals were studied again by cMRI at 8 and 16 weeks following disease induction, and finally by measurement of ex vivo cardiac function.
Results
After eight weeks diabetes, rats (DIA/TETA-DIA) had developed significant impairment of LV function, as judged by impairment of ejection fraction (LVEF), cardiac output (CO), and LV mass (LVM)/body-mass (all P < 0.001), as well as other functional indexes. LVEF, CO (both P < 0.001) and the other indexes deteriorated further at 16 weeks in DIA, whereas trientine (TETA-DIA) improved cardiac function by elevating LVEF and CO (both P < 0.001), and also partially reversed the increase in LVM/body-mass (P < 0.05). In ex vivo hearts from DIA, the CO response to increasing preload pressure was deficient compared with SHAM (P < 0.001) whereas the preload-CO relationship was significantly improved in TETA-DIA animals (P < 0.001).
Conclusions
Trientine treatment significantly improved cardiac function in diabetic rats with substantive LV impairment. These results implicate impaired copper regulation in the pathogenesis of impaired cardiac function caused by diabetic cardiomyopathy, and support ongoing studies of trientine treatment in patients with heart failure.
Background:
One of the mechanisms that has been suggested for obesity related metabolic disturbances is obesity-induced inflammation. Pro-inflammatory cytokines generated in adipose tissue can increase hepatic synthesis of inflammation-sensitive plasma proteins (ISPs) including ceruloplasmin (Cp). In this study we aimed to investigate the relation between serum Cp level and obesity.
Methods:
61 persons with body mass index (BMI) ≥ 25 kg/m² (case group) and 61 persons with BMI < 25 kg/m² (control group) were included in this study with a case-control design. Serum Cp levels, triglyceride level, fating blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol and hsCRP were measured in both groups.
Results:
We did not observe any significant association between serum Cp level and BMI in all subjects [OR: 1.02 (CI, 0.967 to 1.07)] and in case (β = 0.012, P = 0.86) and control groups (β = 0.49, P = 0.07) separately. However, in control group, this positive association was marginally significant. We found a positive correlation between serum Cp level and serum triglyceride level.
Conclusion:
Serum Cp level was not related to obesity in this group of subjects. None of the baseline variables could predict obesity in this group of subjects, including serum Cp level, FBS, total cholesterol, LDL and HDL- cholesterols and hsCRP.
We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6 ± 1.0 years, BMI 31.5 ± 0.4 kg/m(2); 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6-6(2)H(2)] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39-56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r(2) = 27-32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations.
Objective Intestinal microflora and inflammatory cell infiltrates play critical roles in the pathogenesis of acute colitis. Ceruloplasmin is an acute-phase plasma protein produced by hepatocytes and activated macrophages, and has ferroxidase with bactericidal activities. The goal is to understand the role of ceruloplasmin in colitis progression in a genetically modified murine model.
Design Experimental colitis was induced in ceruloplasmin null (Cp−/−) and wild-type (WT) mice by dextran sulphate sodium administration. The role of ceruloplasmin was further evaluated by transplantation of WT macrophages into Cp−/− mice.
Results Cp−/− mice rapidly lost weight and were moribund by day 14, while WT mice survived at least 30 days. Colon culture supernatants from Cp−/− mice exhibited elevated levels of TNFα, KC and MCP-1, indicative of increased inflammation and neutrophil and macrophage infiltration. Elevated leucocytes and severe histopathology were observed in Cp−/− mice. Elevated protein carbonyl content was detected in colons from Cp−/− mice suggesting ceruloplasmin antioxidant activity might contribute to its protective function. Unexpectedly, intraperitoneal administration of human ceruloplasmin into Cp−/− mice did not afford protection. Bone marrow transplantation from WT mice or injection of isolated peripheral blood monocytes markedly reduced severity of colitis and morbidity in Cp−/− mice.
Conclusion Macrophage-derived ceruloplasmin contributes importantly to protection against inflammation and tissue injury in acute and chronic experimental colitis. The findings suggest that defects in ceruloplasmin expression or processing may influence the onset or progression of inflammatory bowel disease in patients.
Copper has a role in antioxidant defense, lipid peroxidation, and mitochondrial function, and copper deficiency has been linked to atherogenic dyslipidemia. We aimed to investigate the potential role of copper availability in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).
Patients with NAFLD (n=124) were compared to patients with chronic hepatitis C (n=50), hemochromatosis (n=35), alcoholic liver disease (n=13), autoimmune hepatitis (n=11), and control subjects (n=27). We determined liver and serum copper concentrations with correlation to clinical, histological, and biochemical parameters in humans. The effect of dietary copper restriction on liver histology and intermediary metabolism in rats was investigated.
Hepatic copper concentrations in patients with NAFLD were lower than in control subjects (17.9+/-8.4 vs. 31.4+/-8.2 microg/g; P<0.001) and in patients with other liver diseases (P<0.05 for all liver diseases). In patients with NAFLD, lower liver copper was correlated with more pronounced hepatic steatosis (R=-0.248; P=0.010), fasting glucose (R=-0.245; P=0.008), and components of the metabolic syndrome (MetS; R=0.363; P<0.001). Patients with nonalcoholic steatohepatitis (NASH; n=31) had lower hepatic copper concentrations than those with simple steatosis (n=93; P=0.038). Restriction of dietary copper in rats induced hepatic steatosis and insulin resistance (IR).
Reduced hepatic copper concentrations are found in human NAFLD and are associated with more pronounced hepatic steatosis, NASH, and components of the MetS. The development of hepatic steatosis and IR in response to dietary copper restriction in rats suggests that copper availability may be involved in the development of NAFLD.
Visceral adipose tissue (VAT) is an important risk factor for obesity-related metabolic disorders. Therefore, a reduction in VAT has become a key goal in obesity management. However, VAT is correlated with intrahepatic triglyceride (IHTG) content, so it is possible that IHTG, not VAT, is a better marker of metabolic disease. We determined the independent association of IHTG and VAT to metabolic function, by evaluating groups of obese subjects, who differed in IHTG content (high or normal) but matched on VAT volume or differed in VAT volume (high or low) but matched on IHTG content. Stable isotope tracer techniques and the euglycemic-hyperinsulinemic clamp procedure were used to assess insulin sensitivity and very-low-density lipoprotein-triglyceride (VLDL-TG) secretion rate. Tissue biopsies were obtained to evaluate cellular factors involved in ectopic triglyceride accumulation. Hepatic, adipose tissue and muscle insulin sensitivity were 41, 13, and 36% lower (P < 0.01), whereas VLDL-triglyceride secretion rate was almost double (P < 0.001), in subjects with higher than normal IHTG content, matched on VAT. No differences in insulin sensitivity or VLDL-TG secretion were observed between subjects with different VAT volumes, matched on IHTG content. Adipose tissue CD36 expression was lower (P < 0.05), whereas skeletal muscle CD36 expression was higher (P < 0.05), in subjects with higher than normal IHTG. These data demonstrate that IHTG, not VAT, is a better marker of the metabolic derangements associated with obesity. Furthermore, alterations in tissue fatty acid transport could be involved in the pathogenesis of ectopic triglyceride accumulation by redirecting plasma fatty acid uptake from adipose tissue toward other tissues.
Obesity is a leading risk factor for metabolic syndrome whose further expression is non-alcoholic fatty liver disease. Metabolic syndrome is associated with a proinflammatory state that contributes to insulin resistance. Finally, a "metabolically benign obesity" that is not accompanied by insulin resistance has recently been postulated to exist.
To find whether any inflammation markers were independently associated with the presence of insulin resistance, evaluating specific anthropometric, ultrasonographic and laboratory parameters in a population of young adult obese subjects.
Of forty two young individuals, divided into two groups (with or without insulin resistance), were studied serum C-reactive protein and fibrinogen as indexes of chronic pro-inflammatory status. Body mass index, waist circumference and metabolic syndrome presence were assessed as part of the metabolic evaluation. Ultrasonography weighted visceral and subcutaneous abdominal fat thickness, spleen size as longitudinal diameter and liver hyperechogenicity.
Serum C-reactive protein and fibrinogen as well as spleen longitudinal diameter were significantly increased in the obese young with insulin resistance compared to non-insulin resistance group. Insulin resistance was significantly associated with hepatic steatosis score at sonography (r = 0.33, P = 0.03), spleen longitudinal diameter (r = 0.35, P = 0.02) and C-reactive protein (r = 0.38, P = 0.01), but not with body mass index, visceral or subcutaneous abdominal adipose tissue, waist circumference and fibrinogen (P = 0.18, 0.46, 0.33, 0.37 and 0.4, respectively). Steatosis score at sonography was well associated with spleen volume (rho = 0.40, P = 0.01) and C-reactive protein levels (rho = 0.49, P = 0.002). Metabolic syndrome was much more frequent in obese patients with insulin resistance. These findings show that in young adults the only abdominal adiposity without insulin resistance, plays a scarce role in determining hepatic steatosis as well as metabolic syndrome.
Increases in spleen size and CRP levels represent a reliable tool in diagnosing insulin resistance.
The plasma copper protein ceruloplasmin (CP) was found to inhibit endothelial nitric-oxide synthase activation in cultured endothelial cells, in line with previous evidence showing that the endothelium-dependent vasorelaxation of the aorta is impaired by physiological concentrations of ceruloplasmin. The data presented here indicate a direct relationship between the extent of inhibition of agonist-triggered endothelial nitric oxide synthase activation and CP-induced enrichment of the copper content of endothelial cells. Copper discharged by CP was mainly localized in the soluble fraction of cells. The subcellular distribution of the metal seems to be of relevance to the inhibitory effect of CP, because it was mimicked by copper chelates, like copper-histidine, able to selectively enrich the cytosolic fraction of cells, but not by copper salts, which preferentially located the metal to the particulate fraction.
Prior studies have provided evidence of marginal dietary copper restriction in humans. The present study was undertaken to examine in a rat model the effect of a long-term marginal dietary Cu deficiency on the heart. Male adult Sprague-Dawley rats were fed AIN-76 diet containing 6.0 (control), 3.0, or 1.5 mg Cu/kg starting at 11 wk of age. Groups of rats were killed at 6, 9, 12, 15, or 18 mo after initiation of feeding, and the same experiment was repeated once. The only systemic change induced by marginal dietary Cu restriction (P < 0.05) was depression of organ Cu concentrations in rats fed 1.5 mg Cu/kg diet. Cardiac pathological manifestations in rats fed lower Cu diets were evidenced by histopathological, ultrastructural, and functional alterations. Myocyte hypertrophy and excessive collagen deposition in the heart occurred in rats fed 1.5 mg Cu/kg diet. Ultrastructural changes, including increased number and volume of mitochondria along with disruption of cristae structure, diastolic and systolic dysfunction, and electrocardiograph alterations, occurred in rats fed 1.5 or 3.0 mg Cu/kg diet. These results demonstrate that, in the absence of most indications of systemic Cu deficiency, heart morphology and function are sensitive to marginal Cu deficiency.
Much experimental evidence demonstrates that the increased production of free radicals and oxidative damage due to alterations in copper homeostasis (because of either deficit or excess or aberrant coordination of the metal) are involved in the neurodegenerative processes occurring in many disorders of the central nervous system. This review outlines the systems that are involved in copper homeostasis and in the control of copper redox reactivity. The mechanisms underlying neurodegeneration in the acknowledged genetic disturbances of copper homeostasis, namely Menkes' and Wilson's diseases, and the involvement of copper in the aetiology of the major neurodegenerative disease of the aging brain, Alzheimer's disease, will be described, with particular focus on oxidative stress.
Continuing Medical Education Course for “Use of Carotid Ultrasound to Identify Subclinical Vascular Disease and Evaluate Cardiovascular Disease Risk: A Consensus Statement for the American Society of Echocardiography Carotid Intima-Media Thickness Task Force”
Accreditation Statement
The American Society of Echocardiography is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The American Society of Echocardiography designates this educational activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
ARDMS and CCI recognize ASE’s certificates and have agreed to honor the credit hours toward their registry requirements for sonographers.
The American Society of Echocardiography is committed to resolving all conflict of interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated.
Target Audience
1. Physicians, physicians’ assistants, and nurses with an interest in cardiac and vascular imaging, preventive cardiology, and cardiovascular disease risk assessment. 2. Ultrasonographers with interest in vascular imaging and cardiovascular disease risk assessment.
Objectives
Upon completing this activity, participants will be able to: 1. Describe the rationale for using carotid ultrasound to identify subclinical vascular disease and to evaluate cardiovascular disease risk. 2. Explain the application of carotid ultrasound to cardiovascular disease risk assessment. 3. Describe the scanning technique for identifying subclinical vascular disease using carotid ultrasound. 4. Explain the key components of interpreting carotid ultrasound studies for cardiovascular disease risk assessment.
Authors Disclosures
James H. Stein, MD, FASE:
Research grants: Siemens Medical Solutions, Sonosite
Intellectual property: listed as the inventor of Patent #US 6,730,0235 “Ultrasonic Apparatus and Method for Providing Quantitative Indication of Risk of Coronary Heart Disease.” It has been assigned to the Wisconsin Alumni Research Foundation.
Emile R. Mohler III, MD:
Speakers bureau for Merck, BMS-Sanofi and AstraZeneca; Research grant support from BMS-Sanofi, Pfizer and GSK.
Christopher M. Rembold, MD:
Advisory Board for Sonosite.
Estimated Time to Complete This Activity: 1 hour
Lysyl oxidase (LOX) plays a crucial role in the maintenance of extracellular matrix stability and could participate in vascular remodelling associated with cardiovascular diseases. Evidence from in vitro and in vivo studies shows that LOX downregulation is associated with the endothelial dysfunction characteristic of earlier stages of the atherosclerotic process. Conversely, upregulation of this enzyme in vascular cells could induce neointimal thickening in atherosclerosis and restenosis. In fact, LOX is chemotactic for vascular smooth muscle cells and monocytes, is modulated by proliferative stimulus in these cells, and could control other cellular processes such as gene expression and cell transformation. Furthermore, it is conceivable that LOX downregulation could underlie plaque instability and contribute to the destructive remodelling that takes place during aneurysm development. Overall, LOX could play a key role in vascular homeostasis and, hence, it emerges as a new player in cardiovascular diseases. This review addresses the experimental evidence related to the role of LOX in vascular disorders and the potential benefits of controlling its expression and function.
We carried out a meta-analysis about non-alcoholic fatty liver disease, carotid artery intima-media thickness and carotid artery plaque to explore the association between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis.
We searched for case-control studies about the relationship between NAFLD and carotid intima-media thick (IMT) published from 2004 to 2014 according to inclusion and exclusion criteria and extracted the relevant data. Statistical analysis was processed by RevMan 5.2 software.
9 studies were involved totally, including 2446 subjects (925 patients and 1521 controls). We found that there was a significant heterogeneity between NAFLD and carotid IMT. By the random effects model we calculated and combined the mean value of carotid IMT. The mean difference was 0.16 mm with 95% confidence interval (0.11, 0.21). Studies showed that there was also heterogeneity between carotid artery plaque and NAFLD. By the random effects model the calculated and combined OR value was 3.73 with 95% confidence interval (2.42, 5.74). The publication bias of the included studies did not exist.
The IMT in NAFLD patients increased 0.16 mm compared with the control group, and risk of carotid plaque was 3.73 times than that of the controls. It is necessary for NAFLD patients to carry out routine carotid ultrasound detection to predict the occurrence of carotid atherosclerosis and assess the risk of cardiovascular disease.
Obesity continues to be a growing issue in the United States, with an estimated prevalence of 72 million people. There are major health implications associated with obesity, including its relationship with hypertension, diabetes mellitus type 2, metabolic syndrome, and dyslipidemia, all independent risk factors for coronary artery disease (CAD). Despite the increased risk of developing CAD, in recent years an "obesity paradox" has been described in which moderately obese individuals with established cardiovascular disease, including CAD, appear to have mortality similar to their normal-weight counterparts. This review examines the relationship between obesity and CAD, including the increased risk of hypertension, diabetes mellitus, metabolic syndrome, and dyslipidemia, along with a discussion of the obesity paradox and the benefits of weight reduction.
Objective:
One potential mechanism through which obesity exerts adverse effects on the vascular system is by increasing aortic stiffness, a change known to be predictive of increased cardiovascular mortality. The aim of this study was to investigate the pathophysiology that links obesity to aortic stiffening.
Approach and results:
Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans.
Conclusions:
Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity.
Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.
This study aimed to investigate new biomarkers of obesity particularly in relation with inflammation-associated proteins using protein differential display techniques.
Comparison of protein expression in plasma between non-obese (n=109, body mass index, BMI<25kg/m(2)) and obese (n=32, BMI≥25kg/m(2)) groups was carried out using two-dimensional gel electrophoresis (2-DE) analysis. ELISA was also performed for validation.
Among six differentially expressed protein spots, ceruloplasmin (Cp) and fibrinogen were over-expressed in obese group. Plasma Cp levels were significantly higher in obese group than non-obese group (34.0 ± 8.6 vs. 41.3 ± 12.7mg/dL, p<0.001) and positively correlated with age (r=0.253, p<0.005), BMI (r=0.265, p<0.001) and hsCRP (r=0.385, p<0.001). In stepwise multiple linear regression analysis, plasma Cp along with hsCRP were found predictors for obesity (adjusted β-coefficient=0.266, p<0.01).
Elevated plasma Cp levels were significantly associated with obesity, which may be suggested to be a marker of obesity.
To determine the association of atherogenic index of plasma (AIP), the logarithm of molar ratio of triglyceridemia to high-density lipoprotein cholesterol (TG/HDL-cholesterol) with cardiometabolic disorders was investigated in a sample of the Turkish population.
A total of 2676 middle-aged adults were prospectively evaluated with a clinical examination and laboratory tests during 7.8 years' follow-up.
AIP was significantly associated in multiple linear regression analyses with greater apolipoprotein B and lower low-density lipoprotein (LDL)-cholesterol levels, reflecting the presence of smaller LDL particle size. Whereas in men insulin levels, obesity, and nonHDL-cholesterol were major determinants, C-reactive protein (CRP) was the strongest determinant of AIP among women, independent of body mass index. Top quartiles of AIP predicted significantly age-adjusted incident coronary heart disease (CHD) in both sexes, more strongly in women, in whom quartile 3 also was a predictor with a greater than 2-fold relative risk. Associations remained significant after adjustment for CRP and traditional risk factors. AIP significantly predicted diabetes and high blood pressure in both sexes after adjustment for age and CRP. With regard to incident high blood pressure, the risk ratio in men was attenuated when body mass index also was adjusted.
High AIP, a surrogate of small LDL particle size, reflects obesity and hyperinsulinemia in men and high CRP status in women. It predicts CHD independently, type 2 diabetes mediated by obesity in men and in women, high blood pressure, metabolic syndrome, and CHD potentially mediated by involvement in a proinflammatory status reflected by CRP.
to the editor: Basciano et al. ([3][1]) found glucose intolerance, hypercholesterolemia, and hypertriglyceridemia plus numerous other changes related to the development of diabetes mellitus and the metabolic syndrome in hamsters fed diets high in fructose and enriched with cholesterol; they
Insulin resistance is supposed to be the basis of metabolic syndrome (MS), although it is difficult to measure. The ratio of triglyceride (TG) to high-density lipoprotein (HDL) has been proposed as a surrogate marker of insulin resistance in overweight subjects. The aim of the present study was to assess the accuracy of the TG/HDL ratio for the diagnosis of MS. Data of 18,778 active workers (77.6% men) enrolled in 3 insurance companies in Spain were collected from their annual health examinations. Mean age was 42.2 +/- 10.7 years. MS was assessed according to modified Adult Treatment Panel III criteria. Prevalences of MS were 18.8% in men and 6.1% in women. Mean value of the TG/HDL ratio was 2.50 +/- 2.2 and increased in parallel to the number of MS components present. Subjects with MS had a ratio that was 2 times higher compared with those without (5.10 vs 2.03, p <0.001). Receiver operating characteristic curves were performed to assess the capability of the TG/HDL ratio to contribute to a diagnosis of MS and 80% sensitivity and 78% specificity were obtained for values >2.75 in men and >1.65 in women. In conclusion, the TG/HDL ratio is a feasible and accurate measurement for assessment of MS in healthy subjects. We propose cut-off values of 2.75 for men and 1.65 for women for a diagnosis of MS.
Experimental inflammation in copper (Cu)-deficient rats is greater than that induced in controls eating normal diet. Cu-supplementation of the Cu-deficient diet results in a reduced swelling, down to normal levels. Injection of the naturally occurring acute phase reactant, ceruloplasmin (Cp) a Cu-bearing serum protein, also results in reduction of experimental inflammation. Since a rise in serum Cp occurs in normal pregnancy this protective anti-inflammatory action of Cp is proposed as an explanation for the widely-observed phenomenon of spontaneous control of rheumatoid arthritis in pregnancy.
Agonist challenged aortic prostacyclin production was examined in copper-adequate, -marginal and -deficient rats fed AIN-based diets providing 6.7, 1.7 and 0.8 micrograms Cu/g, respectively. Aortic rings were incubated in Krebs-Henseleit salts, 10 mmol/L HEPES buffer, pH 7.4, 95%:5% O2:CO2, 37 degrees C, and equilibrated for 1 h. Equilibrated rings were challenged with buffer (basal), 273.0 nmol/L thrombin and angiotensin II at 84.6 pmol/L and 846.0 pmol/L. Prostacyclin production, determined at 10 minutes by RIA as 6-keto prostaglandin F1 alpha, in basal and 84.6 pmol/L angiotensin II ring incubations was significantly reduced by 28 to 48% in copper-deficient rats. With thrombin or 846.0 pmol/L angiotensin II prostacyclin production was significantly reduced by 18 to 55% in copper-marginal and copper-deficient rats. Copper-dependent superoxide dismutase activity was significantly depressed by 30 and 57% in aortae of copper-marginal and copper-deficient rats. Lipid peroxidation, estimated by the thiobarbituric acid test, was significantly increased by 85% in copper-deficient rats, with a nonsignificant 40% increase in aortae from copper-marginal rats. The results suggest that the decreases in aortic prostacyclin production in aortae from both copper-deficient and copper-marginal rats are associated, in a dose-dependent manner, with copper-dependent superoxide dismutase depression and increases in aortic lipid peroxidation.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
The human gastrointestinal system can absorb 30-40% of ingested copper from the typical diets consumed in industrialized countries. Experimental data support the existence of a carrier-mediated transport mechanism with an affinity constant in the micromolar range. Aging probably decreases the efficiency of copper homeostasis, resulting in higher plasma copper concentrations in the elderly. Physiologic differences may account for the higher cupremia of females. Supplements of minerals with similar chemical characteristics could reduce copper absorption. This property has pharmacologic applications in Wilson disease. Manipulation of the fiber content of the diet may have an indirect effect on copper bioavailability by altering the bioavailability of mineral antagonists. Proteins and soluble carbohydrates tend to improve copper absorption and bioavailability by enhancing its solubility and intestinal bulk flow. Organic acids, other than ascorbic acid, or agents that form low-molecular-weight chelates, are likely to have a positive effect on overall copper absorption. Conditions associated with malabsorption of macronutrients and gastrointestinal disease can impair copper uptake and contribute to suboptimal copper status.
There is evidence that copper and zinc have pro-oxidant and antioxidant properties, respectively, so that their imbalance may be expected to condition oxidative stress status. Oxidative stress is relevant in aging and in age-related degenerative diseases. In this study, blood content of copper, zinc, and ceruloplasmin as well as of lipid peroxides were investigated in 81 healthy and 62 disabled octo-nonagenarians affected by chronic degenerative diseases, and in 81 healthy adults. Serum copper/zinc ratio and ceruloplasmin were significantly higher in the elderly than in the healthy adults. Moreover, all these parameters were significantly higher in the disabled than in the healthy elderly. Notably, the increased copper/zinc ratio found in healthy elderly was due to high copper values, whereas in the disabled, both high copper and low serum zinc concentrations were present. The copper/zinc ratio was significantly and positively related to systemic oxidative stress status in all groups. The higher the serum copper/zinc ratio the higher the lipid peroxides plasma content. We conclude that there is a strict relationship between copper/zinc ratio and systemic oxidant burden. Moreover, advanced age and, particularly, advanced age-related chronic degenerative diseases are associated with a significant increase in the copper/zinc ratio and systemic oxidative stress.
Copper is an essential trace element in the maintenance of the cardiovascular system. Copper-deficient diets can elicit, in animals, structural and functional changes that are comparable to those observed in coronary heart disease. In this study, the effect of dietary-induced copper deficiency on aortic lesion development was measured by quantitative image analysis in C57BL/6 mice that are susceptible to diet-induced aortic lesions. The diets administered were severely copper deficient (0.2 mg/kg diet), marginally deficient (0.6 mg/kg diet), or copper adequate (6.0 mg/kg diet). Similarly, increased aortic lesion areas and elevated serum cholesterol were demonstrated in both deficient groups, compared with the copper-adequate group. Evidence for graded differences in copper status among the dietary groups was shown by the dose-response increase in liver copper concentration, copper-zinc superoxide dismutase and cytochrome-c oxidase activities, together with serum caeruloplasmin oxidase with increasing intakes of dietary copper. Despite the difference in copper status between the copper marginal and severely deficient groups, similar lesions found in both groups of mice suggest a threshold effect of copper deficiency on lesion formation.
Early atherosclerosis involves the endothelium of many arteries. Information about peripheral arterial anatomy and function derived from vascular imaging studies such as brachial artery reactivity (BAR) and carotid intima media thickness (IMT) may be pertinent to the coronary circulation. The prevention and early treatment of atherosclerosis is gaining more attention, and these tests might be used as indications or perhaps guides to the effectiveness of therapy, but their application in clinical practice has been limited. This review seeks to define the anatomy and pathophysiology underlying these investigations, their methodology, the significance of their findings, and the issues that must be resolved before their application.
The literature on BAR and IMT is extensively reviewed, especially in relation to clinical use.
Abnormal flow-mediated dilation is present in atherosclerotic vessels, is associated with cardiovascular risk factors, and may be a marker of preclinical disease. Treatment of known atherosclerotic risk factors has been shown to improve flow-mediated dilation, and some data suggest that vascular responsiveness is related to outcome. Carotid IMT is associated with cardiovascular risk factors, and increased levels can predict myocardial infarction and stroke. Aggressive risk factor management can decrease IMT.
BAR and IMT are functional and structural markers of the atherosclerotic process. The clinical use of BAR has been limited by varying reproducibility and the influence by exogenous factors, but IMT exhibits less variability. A desirable next step in the development of BAR and IMT as useful clinical tools would be to show an association of improvement in response to treatment with improvement in prognosis.
Specialised copper sites have been recruited during evolution to provide long-range electron transfer reactivity and oxygen binding and activation in proteins destined to cope with oxygen reactivity in different organisms. Ceruloplasmin is an ancient multicopper dase evolved to insure a safe handling of oxygen in some metabolic pathways of vertebrates. The presently available knowledge of its structure provides a glimpse of its plasticity, revealing a multitude of binding sites that point to an elaborate mechanism of multifunctional activity. Ceruloplasmin represents an example of a 'moonlighting' protein that overcomes the one gene-one structure-one function concept to follow the changes of the organism in its physiological and pathological conditions.
Although active smoking acutely increases arterial stiffness, the association between arterial stiffness and chronic exposure to environmental tobacco smoke (ETS) has not been evaluated. We used baseline data from the Vitamin E Atherosclerosis Prevention Study to evaluate the association between ETS exposure and arterial stiffness among 227 healthy adult nonsmokers.
B-mode ultrasonograms of the common carotid artery were used to compute the carotid arterial wall stiffness index beta. Beta was compared by the number of sources and daily hours of ETS exposure.
The carotid stiffness index beta was positively associated with age, body mass index (BMI), fasting glucose, and common carotid artery intima-media thickness (IMT). In the total sample, beta was not related to the number of ETS exposure sources. The carotid stiffness index beta increased with number of sources and daily hours of ETS in subjects with BMI > or =27.1 kg/m2 and IMT > or =0.707 mm. The association was not apparent in subjects with lower BMI or IMT (for number of ETS sources, interaction P values=0.006 and 0.01, respectively). For number of ETS sources, but not hours of exposure, positive associations were apparent among females (but not males) and among subjects > or =55 years old (but not younger subjects).
These data indicate that arterial stiffness is adversely associated with ETS in a dose-dependent manner among individuals with higher BMI and greater carotid artery IMT.
The involvement of transition metals in atherosclerosis is controversial. Some epidemiological studies have reported a relationship between iron (Fe) and cardiovascular disease, whereas others have not. Experimental studies have reported elevated levels of iron and copper (Cu) in diseased human arteries but have often used methods that release metal ions from proteins.
In this study, we have used the minimally invasive technique of electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICPMS) to quantify iron and copper in ex vivo healthy human arteries and carotid lesions. The EPR spectra detected are characteristic of nonheme Fe(III) complexes. Statistically elevated levels of iron were detected in the intima of lesions compared with healthy controls (0.370 versus 0.022 nmol/mg tissue for EPR, 0.525 versus 0.168 nmol/mg tissue by ICPMS, P<0.05 in each cases). Elevated levels of copper were also detected (7.51 versus 2.01 pmol/mg tissue, lesion versus healthy control, respectively, P<0.05). Iron levels did not correlate with the gender or age of the donor, or tissue protein or calcium levels, but cholesterol levels correlated positively with iron accumulation, as measured by EPR.
These data support the hypothesis that iron accumulates in human lesions and may contribute to disease progression.
In the absence of disease, microvessels provide vessel wall nutrients to the tunica media, while the intima is fed by oxygen diffusion from the lumen. As disease evolves and the tunica intima thickens, oxygen diffusion is impaired, and microvessels become the major source for nutrients to the vessel wall. Microvessels serve as a port of entry for inflammatory cells, from the systemic circulation to the nascent atherosclerotic lesion. As disease progress, microvessels also play a role in intraplaque hemorrhage, lipid core expansion, and plaque rupture. In addition, microvessels are also involved in stent restenosis, and plaque regression. Therefore, microvessels are a pivotal component of atherosclerosis, and proper patient risk-stratification in the near future may include the detection of increased neovascularization in atherosclerotic lesions. This review divided in two parts summarizes the current understanding of atherosclerosis neovascularization, starting with the normal anatomy and physiology and progressing to more advanced stages of the disease. We will review the structure and function of vasa vasorum in health and disease, the mechanisms responsible for the angiogenic process, the role of the immune system, including inflammation and Toll-like receptors, and the pathology of microvessels in early atherosclerotic plaques. Furthermore, the review addresses the advanced stages of atherosclerosis, summarizing the progressive role for microvessels during disease progression, red blood cell extravasation, lipid core expansion, plaque rupture, healing, repair, restenosis, and disease regression, offering the clinician a state-of-the-art, bench to bedside approach to neovascularization in human atherosclerosis.
Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumour cells. Copper chelation decreases the secretion of many of these factors. Serum copper levels are upregulated in many human tumours and correlate with tumour burden and prognosis. Copper chelators reduce tumour growth and microvascular density in animal models. New orally active copper chelators have enabled clinical trials to be undertaken, and there are several studies ongoing. A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.
Carotid intima-media thickness (IMT) is increasingly used as a surrogate marker for atherosclerosis. Its use relies on its ability to predict future clinical cardiovascular end points. We performed a systematic review and meta-analysis of data to examine this association.
Using a prespecified search strategy, we identified 8 relevant studies and compared study design, measurement protocols, and reported data. We identified sources of heterogeneity between studies. The assumption of a linear relationship between IMT and risk was challenged by use of a graphical technique. To obtain a pooled estimate of the relative risk per IMT difference, we performed a meta-analysis based on random effects models. The age- and sex-adjusted overall estimates of the relative risk of myocardial infarction were 1.26 (95% CI, 1.21 to 1.30) per 1-standard deviation common carotid artery IMT difference and 1.15 (95% CI, 1.12 to 1.17) per 0.10-mm common carotid artery IMT difference. The age- and sex-adjusted relative risks of stroke were 1.32 (95% CI, 1.27 to 1.38) per 1-standard deviation common carotid artery IMT difference and 1.18 (95% CI, 1.16 to 1.21) per 0.10-mm common carotid artery IMT difference. Major sources of heterogeneity were age distribution, carotid segment definition, and IMT measurement protocol. The relationship between IMT and risk was nonlinear, but the linear models fitted relatively well for moderate to high IMT values.
Carotid IMT is a strong predictor of future vascular events. The relative risk per IMT difference is slightly higher for the end point stroke than for myocardial infarction. In future IMT studies, ultrasound protocols should be aligned with published studies. Data for younger individuals are limited and more studies are required.
High-fat and marginally copper-deficient diets impair heart function, leading to cardiac hypertrophy, increased lipid droplet volume, and compromised contractile function, resembling lipotoxic cardiac dysfunction. However, the combined effect of the two on cardiac function is unknown. This study was designed to examine the interaction between high-fat and marginally copper-deficient diets on cardiomyocyte contractile function.
Weanling male rats were fed diets incorporating a low- or high-fat diet (10% or 45% of kcal from fat, respectively) with adequate (6 mg/kg) or marginally deficient (1.5 mg/kg) copper content for 12 weeks. Contractile function was determined with an IonOptix system including peak shortening (PS), time-to-PS, time-to-90% relengthening, maximal velocity of shortening/relengthening, and intracellular Ca(2+) ([Ca(2+)](I)) rise and decay.
Neither dietary treatment affected blood pressure or glucose levels, although the high-fat diet elicited obesity and glucose intolerance. Both diets depressed PS, maximal velocity of shortening/relengthening, and intracellular Ca(2+) ([Ca(2+)](I)) rise and prolonged time-to-90% relengthening and Ca(2+) decay without an additive effect between the two. Ca(2+) sensitivity, apoptosis, lipid peroxidation, nitrosative damage, tissue ceramide, and triglyceride levels were unaffected by either diet or in combination. Phospholamban (PLB) but not sarco(endo)plasmic reticulum Ca(2+)-ATPase was increased by both diets. Endothelial NO synthase was depressed with concurrent treatments. The electron transport chain was unaffected, although mitochondrial aconitase activity was inhibited by the high-fat diet.
These data suggest that high-fat and marginally copper deficient diets impaired cardiomyocyte contractile function and [Ca(2+)](i) homeostasis, possibly through a similar mechanism, without obvious lipotoxicity, nitrosative damage, and apoptosis.
Lysyl oxidase (LOX) plays a pivotal role in extracellular matrix (ECM) maturation. Furthermore, novel biological functions has been ascribed to LOX, among them cell differentiation, migration, transformation and regulation of gene expression. In this context, it has been suggested that abnormalities of LOX expression could underlie the development of multiple pathological processes including cardiovascular diseases. LOX seems to be crucial in the preservation of endothelial barrier function. In fact, accumulating evidences suggest a role of this enzyme in atherogenesis and endothelial dysfunction triggered by atherosclerotic risk factors and pro-inflammatory cytokines. Indeed, cytokines such as tumour necrosis factor-alpha (TNF-alpha) modulate vascular LOX expression. This cytokine decreases LOX expression and activity in endothelial cells through a transcriptional mechanism that involves TNF receptor-2 and protein kinase C activation. Interestingly, in vivo studies reveal that TNF-alpha causes a down-regulation of vascular LOX expression. Thus, LOX down-regulation seems to be associated to the endothelial dysfunction elicited by multiple pathological factors. LOX rises as a promising target gene for the development of therapeutic strategies in the treatment of cardiovascular diseases.