The nuclear Farnesoid X Receptor (FXR) is a transcription factor critically involved in metabolic homeostasis in the gut-liver axis. FXR activity is mediated by hormonal and dietary signals and ...driven by bile acids (BAs), which are the natural FXR ligands. Given the great physiological importance in BA homeostasis, as well as in the regulation of glucose and lipid metabolism, FXR plays a pivotal role in the pathogenesis of a wide range of disease of the liver, biliary tract and intestine, including hepatic and colorectal cancer. In the last years several studies have shown the relative FXR tissue-specific importance, highlighting synergism and additive effects in the liver and intestine. Gain- and loss-of-FXR-function mouse models have been generated in order to identify the biological processes and the molecular FXR targets. Taking advantage of the knowledge on the structure-activity relationship of BAs for FXR, semi-synthetic and synthetic molecules have been generated to obtain more selective and powerful FXR activators than BAs. This article is part of a Special Issue entitled: Linking transcription to physiology in lipodomics.
•FXR is critically involved in metabolic homeostasis in the gut-liver axis.•Novel FXR modulators are in clinical trials for metabolic diseases.•Tissue-specific FXR transgenic mice increased our understanding in FXR physiology.•FXR is beneficial in metabolic and inflammatory diseases, and supposedly in cancer.
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the commonest liver cancer. It is expected to become the third leading cause of cancer-related deaths in Western ...countries by 2030. Effective pharmacological approaches for HCC are still unavailable, and the currently approved systemic treatments are unsatisfactory in terms of therapeutic results, showing many side effects. Thus, searching for new effective and nontoxic molecules for HCC treatment is of paramount importance. We previously demonstrated that lysophosphatidic acid (LPA) is an important contributor to the pathogenesis of HCC and that lysophosphatidic acid receptor 6 (LPAR6) actively supports HCC tumorigenicity. Here, we screened for novel LPAR6 antagonists and found that two compounds, 4-methylene-2-octyl-5-oxotetra-hydrofuran-3-carboxylic acid (C75) and 9-xanthenylacetic acid (XAA), efficiently inhibit HCC growth, both in vitro and in vitro, without displaying toxic effects at the effective doses. We further investigated the mechanisms of action of C75 and XAA and found that these compounds determine a G1-phase cell cycle arrest, without inducing apoptosis at the effective doses. Moreover, we discovered that both molecules act on mitochondrial homeostasis, by increasing mitochondrial biogenesis and reducing mitochondrial membrane potential. Overall, our results show two newly identified LPAR6 antagonists with a concrete potential to be translated into effective and side effect–free molecules for HCC therapy.
Vascular contribution to cognitive impairment and dementia (VCID) is a clinical label encompassing a wide range of cognitive disorders progressing from mild to major vascular cognitive impairment ...(VCI), which is also defined as vascular dementia (VaD). VaD diagnosis is mainly based on clinical and imaging findings. Earlier biomarkers are needed to identify subjects at risk to develop mild VCI and VaD. In the present meta-analysis, we comprehensively evaluated the role of inflammatory biomarkers in differential diagnosis between VaD and Alzheimer’s disease (AD), and assessed their prognostic value on predicting VaD incidence. We collected literature until January 31, 2021, assessing three inflammatory markers interleukin(IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α from blood or cerebrospinal fluid (CSF) samples. Thirteen cross-sectional and seven prospective studies were included. Blood IL-6 levels were cross-sectionally significantly higher in people with VaD compared to AD patients (SMD: 0.40, 95% CI: 0.18 to 0.62) with low heterogeneity (
I
2
: 41%,
p
= 0.13). Higher IL-6 levels were also associated to higher risk of incident VaD (relative risk: 1.28, 95% CI: 1.03 to 1.59,
I
2
: 0%). IL-6 in CSF was significantly higher in people with VaD compared to healthy subjects (SMD: 0.77, 95% CI: 0.17 to 1.37,
I
2
: 70%), and not compared to AD patients, but due to limited evidence and high inconsistency across studies, we could not draw definite conclusion. Higher blood IL-6 levels might represent a useful biomarker able to differentiate people with VaD from those with AD and might be correlated with higher risk of future VaD.
Hepatocellular carcinoma (HCC) is one of the most frequent tumours worldwide and available drugs are inadequate for therapeutic results and tolerability. Hence, novel effective therapeutic tools with ...fewer side effects are of paramount importance. We have previously shown that Crithmum maritimum ethyl acetate extract exerts a cytostatic effect in HCC cells. Here, we tested whether C. maritimum ethyl acetate extract in combination with half sorafenib IC50 dose ameliorated efficacy and toxicity of sorafenib in inhibiting liver cancer cell growth. Moreover, we investigated the mechanisms involved.
Two HCC cell lines (Huh7 and HepG2) were treated with C. maritimum ethyl acetate extract and half IC50 sorafenib dose usually employed in vitro. Then, cell proliferation, growth kinetics and cell toxicity were analysed together with an investigation of the cellular mechanisms involved, focusing on cell cycle regulation and apoptosis.
Results show that combined treatment with C. maritimum ethyl acetate extract and half IC50 sorafenib dose decreased cell proliferation comparably to full-dose sorafenib without increasing cell toxicity as confirmed by the effect on cell cycle regulation and apoptosis.
These results provide scientific support for the possibility of an effective integrative therapeutic approach for HCC with fewer side effects on patients.
Idiopathic sudden sensorineural hearing loss (ISSHL) is a common otologic emergency whose cause is still unclear. The importance of blood lipids in the pathogenesis of ISSHL is widely reported in ...literature. In fact elevated levels of low density lipoprotein cholesterol (LDL), total cholesterol (TC) and apolipoprotein B (Apo-B) have been proposed as risk factors for this pathology. No correlation has been described between serum lipid parameters and the prognosis of ISSHL. Aim of the present study was to identify prognostic factors associated with hearing recovery in a group of patients affected by ISSHL. Ninety-four patients with the diagnosis of ISSHL hospitalized between March 2013 and October 2014 were included in this study. Patients' blood sampling and hearing assessments were carried out. Patients were divided into two groups as "recovered" and "unrecovered", according to their response to the treatment. We found a statistically significant higher level of total cholesterol in the unrecovered group compared to the recovered one (p = 0.03). None of the other routine laboratory parameters have shown a statistically significant difference between the patients successfully treated and patients with poor outcomes. Total cholesterol concentrations may be a prognostic factor for recovery in ISSHL and should be assessed together with routine tests in patients with this condition. The other routine laboratory parameters seem to have no effect on the development and prognosis of this pathology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Non-alcoholic fatty liver disease (NAFLD) is an emerging and threatening pathological condition, ranging from fatty liver (FL) to chronic steatohepatitis (NASH), liver cirrhosis, and eventually to ...hepatocellular carcinoma (HCC). Recent findings suggest that patients with NAFLD have a higher risk of cardiovascular events and thromboembolism and that this risk is independent of metabolic diseases that are frequently associated with NAFLD, such as diabetes, hyperlipidaemia, and obesity. The vascular involvement of NAFLD might be considered its systemic burden, conditioning higher mortality in patients affected by the disease. These clinical findings suggested the existence of a prothrombotic state in NAFLD, which is partially unexplored and whose underlying mechanisms are to date not completely understood. Here, we review the mechanisms involved in the pathogenesis of the prothrombotic state in NAFLD across the progression from the healthy liver through the different stages of the disease. We focused on the possible role of several metabolic features of NAFLD possibly leading to hypercoagulation other than endothelial and platelet activation, such as insulin-resistance, nitric oxide production regulation, and gut microbiota homeostasis. Also, we analysed the involvement of plasminogen activator inhibitor-1 (PAI-1) and thromboinflammation taking place in NAFLD. Finally, we described factors striking a prothrombotic imbalance in NASH cirrhosis, with a particular focus on the pathogenesis of portal vein thrombosis.
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•NAFLD could be associated with atherothrombosis and thromboembolism.•This association seems to be independent of obesity, diabetes, and hyperlipidaemia.•Metabolic features of NAFLD may lead to a prothrombotic state and hypercoagulation.•Increased PAI-1 levels and inflammation support the prothrombotic state in NAFLD.•NASH-cirrhosis is associated with a high rate of systemic thrombosis and the portal system.
Genetic heterogeneity is a well-recognized feature of hepatocellular carcinoma (HCC). The coexistence of multiple genetic alterations in the same HCC nodule contributes to explain why gene-targeted ...therapy has largely failed. Targeting of early genetic alterations could theoretically be a more effective therapeutic strategy preventing HCC. However, the failure of most targeted therapies has raised much perplexity regarding the role of genetic alterations in driving cancer as the main paradigm. Here, we discuss the methodological and conceptual limitations of targeting genetic alterations and their products that may explain the limited success of the novel mechanism-based drugs in the treatment of HCC. In light of these limitations and despite the era of the so-called “precision medicine,” prevention and early diagnosis of conditions predisposing to HCC remain the gold standard approach to prevent the development of this type of cancer. Finally, a paradigm shift to a more systemic approach to cancer is required to find optimal therapeutic solutions to treat this disease.
Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic ...transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic-Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells "revert" to "primitive" characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells' metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a "shift" toward "atavistic" biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection.
Background
During the recent lockdown measures adopted by national authorities to contain the COVID-19 pandemic, many vulnerable older patients with chronic conditions, normally followed in ...ambulatory setting, needed to be monitored and managed in alternative ways, including telemedicine.
Aims
In the framework of a telemedicine program, we aimed to validate and implement a telephone-administered version of the Multidimensional Prognostic Index (TELE-MPI) among community-dwelling older outpatients.
Method
From March 9 to May 11, 2020, 131 older patients (82.1 years; 74% females) were interviewed using a telephone-based survey to calculate the TELE-MPI. The standard MPI was performed face-to-face three months apart. The Bland–Altman methodology measured the agreement between the two tools. Multivariate logistic regression models were built to ascertain the prognostic value of TELE-MPI and TELE-MPI classes (low, moderate, or severe risk) on negative outcomes occurring during the lockdown period.
Results
Mean MPI and TELE-MPI values were 0.523 and 0.522, respectively. Lower and upper 95% limits of agreement were − 0.122 and + 0.124, respectively, with only 4.6% of observations outside the limits. Each 0.1 increase of TELE-MPI score was significantly correlated with higher incidence of psychiatric disorders odd ratio (OR): 1.57; 95% confidence interval (CI) 1.27, 1.95 and falls (OR: 1.41; 95% CI 1.08, 1.82) in community-dwelling-older adults.
Discussion
TELE-MPI showed a strong agreement with the standard MPI and was able to predict psychiatric disorders and falls during lockdown period.
Conclusion
TELE-MPI may represent a useful way to follow by remote the health status of older adults.
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