α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells

Hepatocellular carcinoma (HCC) is the most common liver cancer and a major cause of adult death. The current treatments for HCC suffer from drug resistance and poor prognosis; therefore, novel therapeutic agents are urgently needed. Phytochemicals have been proposed to treat a range of cancers. Among them, α-lipoic acid (α-LA), a naturally synthesized antioxidant found in various dietary animal and plant sources, prevents oxidant-mediated cell death in normal cells while inducing apoptosis in several cancer cell lines. Previously, we demonstrated that the treatment of hepatoma cells with α-LA induced apoptosis, which was preceded by the generation of reactive oxygen species (ROS) and activation of the p53 protein, a known inducer of mitochondria-mediated apoptosis. Several studies have shown that ROS-induced apoptosis is associated with endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) activation. Herein, we investigated if α-LA-induced apoptosis in hepatoma cell lines was ER stress- and UPR-mediated by gene expression profiling analyses. UPR and ER stress pathways were the most up-regulated after treatment with α-LA. This finding, which has been confirmed by expression analyses of ER- and UPR-associated proteins, provides a better understanding of the molecular mechanisms behind the anti-tumoral action of α-LA on hepatoma cells

Metabolomics and psychological features in fibromyalgia and electromagnetic sensitivity

Fibromyalgia (FM) as Fibromyalgia and Electromagnetic Sensitivity (IEI-EMF) are a chronic and systemic syndrome. The main symptom is represented by strong and widespread pain in the musculoskeletal system. The exact causes that lead to the development of FM and IEI-EMF are still unknown. Interestingly, the proximity to electrical and electromagnetic devices seems to trigger and/or amplify the symptoms. We investigated the blood plasma metabolome in IEI-EMF and healthy subjects using 1H NMR spectroscopy coupled with multivariate statistical analysis. All the individuals were subjected to tests for the evaluation of psychological and physical features. No significant differences between IEI-EMF and controls relative to personality aspects, Locus of Control, and anxiety were found. Multivariate statistical analysis on the metabolites identified by NMR analysis allowed the identification of a distinct metabolic profile between IEI-EMF and healthy subjects. IEI-EMF were characterized by higher levels of glycine and pyroglutamate, and lower levels of 2-hydroxyisocaproate, choline, glutamine, and isoleucine compared to healthy subjects. These metabolites are involved in several metabolic pathways mainly related to oxidative stress defense, pain mechanisms, and muscle metabolism. The results here obtained highlight possible physiopathological mechanisms in IEI-EMF patients to be better defined

Glutamine Starvation Affects Cell Cycle, Oxidative Homeostasis and Metabolism in Colorectal Cancer Cells

Cancer cells adjust their metabolism to meet energy demands. In particular, glutamine addiction represents a distinctive feature of several types of tumors, including colorectal cancer. In this study, four colorectal cancer cell lines (Caco-2, HCT116, HT29 and SW480) were cultured with or without glutamine. The growth and proliferation rate, colony-forming capacity, apoptosis, cell cycle, redox homeostasis and metabolomic analysis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, high-performance liquid chromatography and gas chromatography/mass spectrometry techniques. The results show that glutamine represents an important metabolite for cell growth and that its deprivation reduces the proliferation of colorectal cancer cells. Glutamine depletion induces cell death and cell cycle arrest in the GO/G1 phase by modulating energy metabolism, the amino acid content and antioxidant defenses. Moreover, the combined glutamine starvation with the glycolysis inhibitor 2-deoxy-D-glucose exerted a stronger cytotoxic effect. This study offers a strong rationale for targeting glutamine metabolism alone or in combination with glucose metabolism to achieve a therapeutic benefit in the treatment of colon cancer

Metabolic Alteration in Plasma and Biopsies From Patients With IBD

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract, with periods of latency alternating with phases of exacerbation, and include 2 forms: Crohn disease (CD) and ulcerative colitis (UC). Although the etiology of IBD is still unclear, the identification and understanding of pathophysiological mechanisms underlying IBD could reveal newly targeted intestinal alterations and determine therapeutic approaches.METHODS: In this study, by using gas chromatography-mass spectrometry, we characterized plasma and biopsies from the metabolomics profiles of patients with IBD compared with those of a control group.RESULTS: The results showed a different metabolomics profile between patients with CD (n = 50) and patients with UC (n = 82) compared with the control group (n = 51). Multivariate statistical analysis of the identified metabolites in CD and UC showed changes in energetic metabolism, and lactic acid and ornithine in particular were altered in both plasma and colon biopsies. Moreover, metabolic changes were evidenced between the normal ileum and colon tissues. These differences disappeared when we compared the inflamed ileum and colon tissues, suggesting a common metabolism.CONCLUSIONS: This study showed how the metabolomics profile could be a potential tool to identify intestinal alterations associated with IBD and may have application in precision medicine and for better defining the pathogenesis of the disease

Vitamin C Cytotoxicity and Its Effects in Redox Homeostasis and Energetic Metabolism in Papillary Thyroid Carcinoma Cell Lines.

High-dose of vitamin C (L-ascorbic acid, ascorbate) exhibits anti-tumoral effects, primarily mediated by pro-oxidant mechanisms. This cytotoxic effect is thought to affect the reciprocal crosstalk between redox balance and cell metabolism in different cancer types. Vitamin C also inhibits the growth of papillary thyroid carcinoma (PTC) cells, although the metabolic and redox effects remain to be fully understood. To shed light on these aspects, PTC-derived cell lines harboring the most common genetic alterations characterizing this tumor were used. Cell viability, apoptosis, and the metabolome were explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, and UHPLC/MS. Changes were observed in redox homeostasis, with increased reactive oxygen species (ROS) level and perturbation in antioxidants and electron carriers, leading to cell death by both apoptosis and necrosis. The oxidative stress contributed to the metabolic alterations in both glycolysis and TCA cycle. Our results confirm the pro-oxidant effect of vitamin C as relevant in triggering the cytotoxicity in PTC cells and suggest that inhibition of glycolysis and alteration of TCA cycle via NAD+ depletion can play an important role in this mechanism of PTC cancer cell death

Small-bowel capsule endoscopy with panoramic view: results of the first multicenter, observational study (with videos).

BACKGROUND AND AIMS: The first small-bowel video-capsule endoscopy (VCE) with 360° panoramic view has been recently developed. This new capsule has a wire-free technology, 4 high frame-rate cameras, and a long-lasting battery life. The present study was aimed at assessing performances and the safety profile of the 360° panoramic-view capsule in a large series of patients from a multicenter clinical practice setting. METHODS: Consecutive patients undergoing a 360° panoramic-view capsule procedure in 7 European Institutions between January 2011 and November 2015 were included. Both technical (ie, technical failures, completion rate) and clinical (ie, indication, findings, retention rate) data were collected by means of a structured questionnaire. VCE findings were classified according to the likelihood to explain reason for referral: P0-low, P1-intermediate and P2-high. RESULTS: Among 172 patients (94 men; median age: 68 years, IQR: 53-75), 142 underwent VCE for obscure (32 overt, 110 occult) GI bleeding (OGIB) and 28 for suspected (17) or established (2) Crohn's disease (CD). Overall, 560 findings were detected; 252 of them were P2. The overall diagnostic yield was 40.1%; 42.2% and 30.0% in patients with OGIB and CD, respectively. The rate of complete enteroscopy was 90.2%. All of the patients but one, who experienced capsule retention (1/172: 0.6%), excreted and retrieved the capsule. VCE failure occurred in 4 of 172 (2.3%) cases for technical problems. CONCLUSION: The present multicenter study, conducted in clinical practice setting and based on a large consecutive series of patients, showed that DY and safety profile of 360° panoramic-view capsule are similar to those of forward-view VCEs

Heme oxygenase-1 inhibitor tin-protoporphyrin improves liver regeneration after partial hepatectomy

AIMS: This study investigates the effects of the heme oxygenase-1 (HO-1) inhibitor tin protoporphyrin IX (SnPP), on rat liver regeneration following 2/3 partial hepatectomy (PH) in order to clarify the controversial role of HO-1 in the regulation of cellular growth. MAIN METHODS: Male Wistar rats received a subcutaneous injection of either SnPP (10 μmoles/kg body weight) or saline 12 h before PH and 0, 12 and 24 h after surgery. Rats were killed from 0.5 to 36 h after PH. Bromodeoxyuridine (BrdU) incorporation was used to analyze cell proliferation. Immunohistochemistry, Western blot analysis and quantitative Real Time-PCR were used to assess molecular and cellular changes after PH. KEY FINDINGS: Data obtained have shown that administration of SnPP caused an increased entry of hepatocytes into S phase after PH, as demonstrated by labeling (L.I.) and mitotic (M.I.) indexes. Furthermore, enhanced cell cycle entry in PH-animals pre-treated with SnPP was associated with an earlier activation of IL-6 and transcription factors involved in liver regeneration, such as phospho-JNK and phospho-STAT3. SIGNIFICANCE: Summarizing, data here reported demonstrate that inhibition of HO-1 enhances rat liver regeneration after PH which is associated to a very rapid increase in the levels of inflammatory mediators such as IL-6, phopsho-JNK and phospho-STAT3, suggesting that HO-1 could act as a negative modulator of liver regeneration. Knowledge about the mechanisms of liver regeneration can be applied to clinical problems caused by delayed liver growth, and HO-1 repression may be a mechanism by which cells can faster proliferate in response to tissue damage

Contribution of Metabolomics to the Understanding of NAFLD and NASH Syndromes: A Systematic Review

Several differential panels of metabolites have been associated with the presence of metabolic syndrome and its related conditions, namely non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This study aimed to perform a systematic review to summarize the most recent finding in terms of circulating biomarkers following NAFLD/NASH syndromes. Hence, the research was focused on NAFLD/NASH studies analysed by metabolomics approaches. Following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic search was conducted on the PubMed database. The inclusion criteria were (i) publication date between 2010 and 2021, (ii) presence of the combination of terms: metabolomics and NAFLD/NASH, and (iii) published in a scholarly peer-reviewed journal. Studies were excluded from the review if they were (i) single-case studies, (ii) unpublished thesis and dissertation studies, and (iii) not published in a peer-reviewed journal. Following these procedures, 10 eligible studies among 93 were taken into consideration. The metabolisms of amino acids, fatty acid, and vitamins were significantly different in patients affected by NAFLD and NASH compared to healthy controls. These findings suggest that low weight metabolites are an important indicator for NAFLD/NASH syndrome and there is a strong overlap between NAFLD/NASH and the metabolic syndrome. These findings may lead to new perspectives in early diagnosis, identification of novel biomarkers, and providing novel targets for pharmacological interventions

The thyromimetic KB2115 (Eprotirome) induces rat hepatocyte proliferation

Although the hepatomitogenic activity of T3 is well established, the wide range of harmful effects exerted by this hormone precludes its use in regenerative therapy. The aim of this study was to investigate whether an agonist of TR, KB2115 (Eprotirome) could exert a mitogenic effect in the liver, without most of the adverse T3/TR-dependent side effects. F-344 rats treated with KB2115 for one week displayed a massive increase in bromodeoxyuridine incorporation (from 20 to 40% vs. 5% of controls), which was associated with increased mitotic activity in the absence of significant signs of liver toxicity. Noteworthy, while cardiac hypertrophy typical of T3 was not observed, beneficial effects, such as lowering blood cholesterol levels, were associated to KB2115 administration. Following a single dose of KB2115, hepatocyte proliferation was evident as early as 18 hours demonstrating its direct mitogenic effect. No increase of serum transaminase levels or apoptosis was observed prior to- or concomitantly with S phase. While KB2115-induced mitogenesis was not associated to enhanced expression of c-fos, c-jun and c-myc, cyclin D1 levels rapidly increased. In conclusion, KB2115 induces hepatocyte proliferation without overt toxicity. Hence this agent may be useful for regenerative therapies in liver transplantation or other surgical settings