The consumption of an olive oil rich diet has been associated with the diminished incidence of cardiovascular disease and cancer. Several studies have attributed these beneficial effects to oleic ...acid (C18 n-9), the predominant fatty acid principal component of olive oil. Oleic acid is not an essential fatty acid since it can be endogenously synthesized in humans. Stearoyl-CoA desaturase 1 (SCD1) is the enzyme responsible for oleic acid production and, more generally, for the synthesis of monounsaturated fatty acids (MUFA). The saturated to monounsaturated fatty acid ratio affects the regulation of cell growth and differentiation, and alteration in this ratio has been implicated in a variety of diseases, such as liver dysfunction and intestinal inflammation. In this review, we discuss our current understanding of the impact of gene-nutrient interactions in liver and gut diseases, by taking advantage of the role of SCD1 and its product oleic acid in the modulation of different hepatic and intestinal metabolic pathways.
Extra virgin olive oil (EVOO) consumption has a beneficial effect on human health, especially for prevention of cardiovascular disease and metabolic disorders. Here we underscore the peculiar ...importance of specific cultivars used for EVOO production since biodiversity among cultivars in terms of fatty acids and polyphenols content could differently impact on the metabolic homeostasis. In this respect, the nutrigenomic approach could be very useful to fully dissect the pathways modulated by different EVOO cultivars in terms of mRNA and microRNA transcriptome. The identification of genes and miRNAs modulated by specific EVOO cultivars could also help to discover novel nutritional biomarkers for prevention and/or prognosis of human disease. Thus, the nutrigenomic approach depicts a novel scenario to investigate if a specific EVOO cultivar could have a positive effect on human health by preventing the onset of cardiovascular disease and/or chronic inflammatory disorders also leading to cancer.
The nuclear receptor farnesoid X receptor (FXR) is the master regulator of bile acids (BAs) homeostasis since it transcriptionally drives modulation of BA synthesis, influx, efflux, and ...detoxification along the enterohepatic axis. Due to its crucial role, FXR alterations are involved in the progression of a plethora of BAs associated inflammatory disorders in the liver and in the gut. The involvement of the FXR pathway in cholestasis development and management has been elucidated so far with a direct role of FXR activating therapy in this condition. However, the recent identification of a new type of genetic progressive familial intrahepatic cholestasis (PFIC) linked to FXR mutations has strengthen also the bona fide beneficial effects of target therapies that by-pass FXR activation, directly promoting the action of its target, namely the enterokine FGF19, in the repression of hepatic BAs synthesis with reduction of total BA levels in the liver and serum, accomplishing one of the major goals in cholestasis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.
•FXR alterations are involved in BAs associated inflammatory disorders in the gut-liver axis.•PFIC is a group of liver disorders characterized by pruritus, malabsorption and liver failure.•NR1H4 mutations lead to a new type of PFIC characterized by intralobular cholestasis in infants.•Mdr2KO, FXRnull and Bsep−/− mice have been used to elucidate the mechanism driving cholestasis.•ASBT inhibitors, FXR agonists and FGF19 mimetic represent the most promising anti-cholestatic strategies.
Over the last decades, a better knowledge of the molecular machinery supervising the regulation of circadian clocks has been achieved, and numerous findings have helped in unravelling the outstanding ...significance of the molecular clock for the proper regulation of our physiologic and metabolic homeostasis. Non-alcoholic fatty liver disease (NAFLD) is currently considered as one of the emerging liver pathologies in the Western countries due to the modification of eating habits and lifestyle. Although NAFLD is considered a pretty benign condition, it can progress towards non-alcoholic steatohepatitis (NASH) and eventually hepatocellular carcinoma (HCC). The pathogenic mechanisms involved in NAFLD development are complex, since this disease is a multifactorial condition. Major metabolic deregulations along with a genetic background are believed to take part in this process. In this light, the aim of this review is to give a comprehensive description of how our circadian machinery is regulated and to describe to what extent our internal clock is involved in the regulation of hormonal and metabolic homeostasis, and by extension in the development and progression of NAFLD/NASH and eventually in the onset of HCC.
Hepatocellular carcinoma (HCC) is an alarming epidemiological clinical problem worldwide. Pharmacological approaches currently available do not provide adequate responses due to poor effectiveness, ...high toxicity, and serious side effects. Our previous studies have shown that the wild edible plant
Crithmum maritimum
L. inhibits the growth of liver cancer cells and promotes liver cell differentiation by reducing lactic acid fermentation (Warburg effect). Here, we aimed to further characterise the effects of
C. maritimum
on lipid metabolism and markers of cellular metabolic health, such as AMP-activated protein kinase (AMPK), Sirtuin 1 (SIRT1), and Sirtuin 3 (SIRT3), as well as the insulin signalling pathway. To better mimic the biological spectrum of HCC, we employed four HCC cell lines with different degrees of tumorigenicity and lactic acid fermentation/Warburg phenotype. Lipid accumulation was assessed by Oil Red O (ORO) staining, while gene expression was measured by real-time quantitative PCR (RT-qPCR). The activation of AMPK and insulin signalling pathways was determined by Western blotting. Results indicate that
C. maritimum
prevents lipid accumulation, downregulates lipid and cholesterol biosynthesis, and modulates markers of metabolic health, such as AMPK, SIRT1 and SIRT3. This modulation is different amongst HCC cell lines, revealing an important functional versatility of
C. maritimum
. Taken together, our findings corroborate the importance of
C. maritimum
as a valuable nutraceutical, reinforcing its role for the improvement of metabolic health.
Musculoskeletal pain (excluding bone cancer pain) affects more than 30% of the global population and imposes an enormous burden on patients, families, and caregivers related to functional limitation, ...emotional distress, effects on mood, loss of independence, and reduced quality of life. The pathogenic mechanisms of musculoskeletal pain relate to the differential sensory innervation of bones, joints, and muscles as opposed to skin and involve a number of peripheral and central nervous system cells and mediators. The interplay of neurons and non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies and sensitizes pain signals in a manner that leads to cortical remodeling. Moreover, sex, age, mood, and social factors, together with beliefs, thoughts, and pain behaviors influence the way in which musculoskeletal pain manifests and is understood and assessed. The aim of this narrative review is to summarize the different pathogenic mechanisms underlying musculoskeletal pain and how these mechanisms interact to promote the transition from acute to chronic pain.
Frailty is a common condition in older people. The epidemiological data available, however, are mainly based on the physical frailty phenotype. An extensive literature has suggested that frailty ...should be identified using a multidimensional approach. Based on these recommendations, we estimated the prevalence of frailty and pre-frailty in the older population, using the multidimensional prognostic index (MPI), a common tool for defining multidimensional frailty. We searched several databases until 10th May 2021 for studies reporting the prevalence of frailty according to MPI values. MPI was categorized, where possible, in < 0.33 (robustness), 0.33–0.66 (pre-frailty) and > 0.66 (frailty) or using a RECursive Partition and AMalgamation approach. A meta-analysis of the prevalence, with the correspondent 95% confidence intervals (CIs) of pre-frailty and frailty was performed stratified by setting (population-based, ambulatory, nursing home, and hospital). Among 177 papers initially screened, we included 57 studies for a total of 56,407 older people. The mean age was 78.6 years, with a slight prevalence of women (58%). The overall prevalence of multidimensional frailty (MPI-3) was 26.8% (95%CI: 22.1–31.5), being higher in nursing home setting (51.5%) and lower in population-based studies (13.3%). The prevalence of pre-frailty (MPI-2) was 36.4% (95%CI: 33.1–39.7), being higher in hospital setting (39.3%) and lower in nursing home (20%). In conclusion, frailty and pre-frailty, according to a multidimensional definition, are common in older people affecting, respectively, one person over four and one over three. Our work further strengths the importance of screening frailty in older people using a multidimensional approach.
•The multidimensional approach to identify frailty is increasing in importance.•In our meta-analysis, using the MPI, we found that overall prevalence of multidimensional frailty (MPI-3) was 26.8%.•The prevalence of frailty was higher in nursing home setting, lower in community.•The prevalence of pre-frailty was 36.4%, being higher in hospital.
Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty (BF) construct, ...estimating its impact on the risk of incident dementia and its subtypes.
In 2171 older individuals from the population-based Italian Longitudinal Study on Aging (ILSA), we identified by latent class procedures the BF construct as the physical frail status plus at least one of the two items of the 30-item Geriatric Depression Scale impaired (items 3/10).
Over a 3.5-year follow-up, participants with BF showed an increased risk of overall dementia (hazard ratio HR: 2.16, 95% confidence interval CI:1.07-4.37), particularly vascular dementia (VaD) (HR: 3.21, 95% CI: 1.05-9.75). Similarly, over a 7-year follow-up, an increased risk of overall dementia (HR: 1.84, 95% CI: 1.06-3.20), particularly VaD (HR: 2.53, 95% CI: 1.08-5.91), was also observed.
In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD.
Hepatocellular carcinoma (HCC) is one of the most threatening tumours in the world today. Pharmacological treatments for HCC mainly rely on protein kinase inhibitors, such as sorafenib and ...regorafenib. Even so, these approaches exhibit side effects and acquired drug resistance, which is an obstacle to HCC treatment. We have previously shown that selective lysophosphatidic acid receptor 6 (LPAR6) chemical antagonists inhibit HCC growth. Here, we investigated whether LPAR6 mediates resistance to sorafenib by affecting energy metabolism in HCC. To uncover the role of LPAR6 in drug resistance and cancer energy metabolism, we used a gain-of-function and loss-of-function approach in 2D tissue and 3D spheroids. LPAR6 was ectopically expressed in HLE cells (HLE-LPAR6) and knocked down in HepG2 (HepG2 LPAR6-shRNA). Measurements of oxygen consumption and lactate and pyruvate production were performed to assess the energy metabolism response of HCC cells to sorafenib treatment. We found that LPAR6 mediates the resistance of HCC cells to sorafenib by promoting lactic acid fermentation at the expense of oxidative phosphorylation (OXPHOS) and that the selective LPAR6 antagonist 9-xanthenyl acetate (XAA) can effectively overcome this resistance. Our study shows for the first time that an LPAR6-mediated metabolic mechanism supports sorafenib resistance in HCC and proposes a pharmacological approach to overcome it.
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•Hepatocellular carcinoma (HCC) is one of the most threatening tumours worldwide.•Acquired resistance to sorafenib is an important issue in the treatment of HCC.•Selective lysophosphatidic acid receptor 6 (LPAR6) antagonists inhibit HCC growth.•LPAR6 mediates sorafenib resistance by modulating the bioenergetic phenotype of HCC cells.•A selective LPAR6 chemical antagonist effectively overcomes sorafenib resistance.
The enzyme stearoyl-coenzyme A desaturase 1 (SCD or SCD1) produces monounsaturated fatty acids by introducing double bonds into saturated bonds between carbons 9 and 10, with oleic acid as the main ...product. SCD1 is present in the intestinal epithelium, and fatty acids regulate cell proliferation, so we investigated the effects of SCD1-induced production of oleic acid in enterocytes in mice.
We generated mice with disruption of Scd1 selectively in the intestinal epithelium (iScd1–/– mice) on a C57BL/6 background; iScd1+/+ mice were used as controls. We also generated iScd1–/–ApcMin/+ mice and studied cancer susceptibility. Mice were fed a chow, oleic acid–deficient, or oleic acid–rich diet. Intestinal tissues were collected and analyzed by histology, reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and mass spectrometry, and tumors were quantified and measured.
Compared with control mice, the ileal mucosa of iScd1–/– mice had a lower proportion of palmitoleic (C16:1 n-7) and oleic acids (C18:1 n-9), with accumulation of stearic acid (C18:0); this resulted a reduction of the Δ9 desaturation ratio between monounsaturated (C16:1 n-7 and C18:1 n-9) and saturated (C16:0 and C18:0) fatty acids. Ileal tissues from iScd1–/– mice had increased expression of markers of inflammation activation and crypt proliferative genes compared with control mice. The iScd1–/–ApcMin/+ mice developed more and larger tumors than iScd1+/+ApcMin/+ mice. iScd1–/–ApcMin/+ mice fed the oleic acid-rich diet had reduced intestinal inflammation and significantly lower tumor burden compared with mice fed a chow diet.
In studies of mice, we found intestinal SCD1 to be required for synthesis of oleate in the enterocytes and maintenance of fatty acid homeostasis. Dietary supplementation with oleic acid reduces intestinal inflammation and tumor development in mice.
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