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Journal ArticleDOI: 10.1007/S00204-021-02974-9

Krebs cycle: activators, inhibitors and their roles in the modulation of carcinogenesis

02 Mar 2021-Archives of Toxicology (Springer Science and Business Media LLC)-Vol. 95, Iss: 4, pp 1161-1178
Abstract: A fundamental metabolic feature of cancerous tissues is high glucose consumption. The rate of glucose consumption in a cancer cell can be 10-15 times higher than in normal cells. Isolation and cultivation of tumor cells in vitro highlight properties that are associated with intensive glucose utilization, the presence of minimal oxidative metabolism, an increase in lactate concentrations in the culture medium and a reduced rate of oxygen consumption. Although glycolysis is suggested as a general feature of malignant cells and recently identified as a possible contributing factor to tumor progression, several studies highlight distinct metabolic characteristics in some tumors, including a relative decrease in avidity compared to glucose and/or a glutamine dependency of lactate and even proliferative tumor cells. The aim of this review is to determine the particularities in the energy metabolism of cancer cells, focusing on the main nutritional substrates, such as glucose and glutamine, evaluating lactate dehydrogenase as a potential marker of malignancy and estimating activators and inhibitors in cancer treatment.

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Topics: Lactate dehydrogenase (56%), Cancer cell (55%), Tumor progression (54%) ... show more
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8 results found


Journal ArticleDOI: 10.1016/J.PHRS.2021.105854
Geir Bjørklund, Lili Zou1, Jun Wang1, Christos T. Chasapis2  +1 moreInstitutions (3)
Abstract: Thioredoxin reductases (TrxRs) belong to the pyridine nucleotide disulfide oxidoreductase family enzymes that reduce thioredoxin (Trx). The couple TrxR and Trx is one of the major antioxidant systems that control the redox homeostasis in cells. The thioredoxin system, comprised of TrxR, Trx and NADPH, exerts its activities via a disulfide-dithiol exchange reaction. Inhibition of TrxR is an important clinical goal in all conditions in which the redox state is perturbed. The present review focuses on the most critical aspects of the cellular functions of TrxRs and their inhibition mechanisms by metal ions or chemicals, through direct targeting of TrxRs or their substrates or protein interactors. To update the involvement of overactivation/dysfunction of TrxRs in various pathological conditions, human diseases associated with TrxRs genes were critically summarized by publicly available genome-wide association study (GWAS) catalogs and literature. The pieces of evidence presented here justify why TrxR is recognized as one of the most critical clinical targets and the growing current interest in developing molecules capable of interfering with the functions of TrxR enzymes.

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Topics: Thioredoxin (58%), Thioredoxin reductase (57%)

3 Citations


Journal ArticleDOI: 10.1016/J.SEMCANCER.2021.06.020
Abstract: Although thousands of different nanoparticles (NPs) have been identified and synthesized to date, well-defined, consistent guidelines to control their exposure and evaluate their potential toxicity have yet to be fully established. As potential applications of nanotechnology in numerous fields multiply, there is an increased awareness of the issue of nanomaterials' toxicity among scientists and producers managing them. An updated inventory of customer products containing NPs estimates that they currently number over 5.000; ten years ago, they were one fifth of this. More often than not, products bear no information regarding the presence of NPs in the indicated list of ingredients or components. Consumers are therefore largely unaware of the extent to which nanomaterials have entered our lives, let alone their potential risks. Moreover, the lack of certainties with regard to the safe use of NPs is curbing their applications in the biomedical field, especially in the diagnosis and treatment of cancer, where they are performing outstandingly but are not yet being exploited as much as they could. The production of radical oxygen species is a predominant mechanism leading to metal NPs-driven carcinogenesis. The release of particularly reactive metal ions capable of crossing cell membranes has also been implicated in NPs toxicity. In this review we discuss the origin, behavior and biological toxicity of different metal NPs with the aim of rationalizing related health hazards and calling attention to toxicological concerns involved in their increasingly widespread use.

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3 Citations


Open accessJournal ArticleDOI: 10.1016/J.LWT.2021.112657
Jing Yu1, Kuan Lu1, Xiufang Dong1, Wancui Xie1Institutions (1)
Abstract: The objective of this study was to investigate the effects of halophilic bacteria, including Virgibacillus sp. ZV10-1, Virgibacillus sp. SK37, and Staphylococcus nepalensis JS11 as starters on physicochemical, sensory, and taste properties of rapidly-fermented shrimp paste. Halophilic bacteria reduced moisture and total volatile basic nitrogen content and increased the pH and amino acid nitrogen content of shrimp pastes. Higher levels of total organic acids (484.47 ± 10.40 mg/100 g) were detected in sample inoculated with S. nepalensis JS11. Assessment of sensory parameters indicated that the three-bacteria compound inoculation group improved taste of shrimp paste effectively and contained the highest level of free amino acids (8930.25 ± 3.51 mg/100 g) and equivalent umami concentration (EUC) (960.32 g MSG/100 g). Furthermore, partial least squares regression analysis demonstrated that rapidly-fermented shrimp pastes were associated with sweetness, umami, color, texture, and overall liking attributes, which were related to the presence of tartaric acid, malic acid, GMP, Glu, Asp, Arg and Thr. Thus, this study highlights the potential of Virgibacillus sp. SK37 and S. nepalensis JS11 for the production of rapidly-fermented shrimp paste with improved taste profiles.

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Topics: Shrimp (57%), Umami (50%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/DIAGNOSTICS11061065
Yu-Hung Chen1, Sung-Chao Chu1, Ling-Yi Wang1, Tso Fu Wang1  +6 moreInstitutions (1)
09 Jun 2021-
Abstract: We investigated whether the combination of primary tumor and nodal 18F-FDG PET parameters predict survival outcomes in patients with nodal metastatic non-small cell lung cancer (NSCLC) without distant metastasis. We retrospectively extracted pre-treatment 18F-FDG PET parameters from 89 nodal-positive NSCLC patients (stage IIB-IIIC). The Cox proportional hazard model was used to identify independent prognosticators of overall survival (OS) and progression-free survival (PFS). We devised survival stratification models based on the independent prognosticators and compared the model to the American Joint Committee on Cancer (AJCC) staging system using Harrell's concordance index (c-index). Our results demonstrated that total TLG (the combination of primary tumor and nodal total lesion glycolysis) and age were independent risk factors for unfavorable OS (p < 0.001 and p = 0.001) and PFS (both p < 0.001), while the Eastern Cooperative Oncology Group scale independently predicted poor OS (p = 0.022). Our models based on the independent prognosticators outperformed the AJCC staging system (c-index = 0.732 versus 0.544 for OS and c-index = 0.672 versus 0.521 for PFS, both p < 0.001). Our results indicate that incorporating total TLG with clinical factors may refine risk stratification in nodal metastatic NSCLC patients and may facilitate tailored therapeutic strategies in this patient group.

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Topics: AJCC staging system (58%), Primary tumor (53%)

1 Citations


Journal ArticleDOI: 10.1016/J.CBI.2021.109704
Mingxia Jiang1, Yiming Wu1, Ling Qi1, Lisha Li1  +5 moreInstitutions (1)
Abstract: Pyroptosis is a novel type of pro-inflammatory programmed cell death that has been strongly reported to be related to inflammation, immune, and cancer. Dihydroartemisinin (DHA) has good anti-tumor properties. However, the exact mechanism by which DHA induces pyroptosis to inhibit esophageal squamous cell carcinoma (ESCC) remains unclear. After applying DHA treatment to ESCC, we found that some dying cells exhibited the characteristic morphology of pyroptosis, such as blowing large bubbles from the cell membrane, accompanied by downregulation of pyruvate kinase isoform M2 (PKM2), activation of caspase-8/3, and production of GSDME-NT. Meanwhile, it was accompanied by an increased release of LDH and inflammatory factors (IL-18 and IL-1β). Both knockdown of GSDME and application of caspase-8/3 specific inhibitors (z-ITED-FMK/Ac-DEVD-CHO) significantly inhibited DHA-induced pyroptosis. However, the former did not affect the activation of caspase-3. In contrast, overexpression of PKM2 inhibited caspase-8/3 activation as well as GSDME-N production. Furthermore, both si-GSDME and OE-PKM2 inhibited DHA-induced pyroptosis in vivo and in vitro. Therefore, the results suggest that DHA can induce pyroptosis of ESCC cells via the PKM2-caspase-8/3-GSDME pathway. Implication: In this study, we identified new mechanism of DHA in inhibiting ESCC development and progression, and provide a potential therapeutic agent for the treatment of ESCC.

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Topics: Pyroptosis (67%), Caspase 8 (50%), Inflammation (50%) ... show more

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149 results found


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1160809
22 May 2009-Science
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

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Topics: Reverse Warburg effect (62%), Warburg effect (58%), Anaerobic glycolysis (56%) ... show more

10,427 Citations


Open accessJournal ArticleDOI: 10.2337/DC14-2441
01 Jan 2015-Diabetes Care
Abstract: In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2). Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

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Topics: Type 2 diabetes (50%)

2,366 Citations


Open accessJournal ArticleDOI: 10.1136/BMJ.38415.708634.F7
02 Jun 2005-BMJ
Abstract: Metformin, widely given to patients with type 2 diabetes, works by targeting the enzyme AMPK (AMP activated protein kinase), which induces muscles to take up glucose from the blood. A recent breakthrough has found the upstream regulator of AMPK to be a protein kinase known as LKB1.1 2 LKB1 is a well recognised tumour suppressor. Activation of AMPK by metformin and exercise requires LKB1, and this would also explain why exercise is beneficial in the primary and secondary prevention of certain cancers.3 We hypothesise that metformin use in patients with type 2 diabetes may reduce their risk of cancer. We tested this hypothesis using record linkage databases developed in Tayside, Scotland: a diabetes clinical information system (DARTS) and a database of dispensed prescriptions (MEMO).4 We did a pilot case-control study using previously validated methods.5 From 314 127 people who were resident (or died) in Tayside in …

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Topics: Metformin (58%), AMPK (58%), Type 2 diabetes (55%) ... show more

2,022 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE11986
11 Apr 2013-Nature
Abstract: Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.

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Topics: Succinate receptor 1 (72%), Oxidative phosphorylation (56%), Citric acid cycle (55%) ... show more

1,902 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1120781
09 Dec 2005-Science
Abstract: The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)–activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element–binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1α expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.

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Topics: CRTC2 (64%), AMPK (64%), Glucose homeostasis (58%) ... show more

1,724 Citations


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