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Fulltext Human soluble CD39 displays substrate inhibition in a substrate-specific manner

Vadlamani VMK, Gunasinghe KKJ, Chee XW, Rahman T, Harper MT

Sci Rep, 2023 Jun 02;13(1):8958.
PMID: 37268726 DOI: 10.1038/s41598-023-36257-3

CD39 (ectonucleoside triphosphate diphosphohydrolase-1; ENTPD1) metabolizes extracellular ATP and ADP to AMP. AMP is subsequently metabolized by CD79 to adenosine. CD39 activity is therefore a key regulator of purinergic signalling in cancer, thrombosis, and autoimmune diseases. In this study we demonstrate that soluble, recombinant CD39 shows substrate inhibition with ADP or ATP as the substrate. Although CD39 activity initially increased with increasing substrate concentration, at high concentrations of ATP or ADP, CD39 activity was markedly reduced. Although the reaction product, AMP, inhibits CD39 activity, insufficient AMP was generated under our conditions to account for the substrate inhibition seen. In contrast, inhibition was not seen with UDP or UTP as substrates. 2-methylthio-ADP also showed no substrate inhibition, indicating the nucleotide base is an important determinant of substrate inhibition. Molecular dynamics simulations revealed that ADP can undergo conformational rearrangements within the CD39 active site that were not seen with UDP or 2-methylthio-ADP. Appreciating the existence of substrate inhibition of CD39 will help the interpretation of studies of CD39 activity, including investigations into drugs that modulate CD39 activity.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext More than a drug target: Purinergic signalling as a source for diagnostic tools in epilepsy

Wong ZW, Engel T

Neuropharmacology, 2023 Jan 01;222:109303.
PMID: 36309046 DOI: 10.1016/j.neuropharm.2022.109303

Epilepsy is one of the most common and disabling chronic neurological diseases affecting people of all ages. Major challenges of epilepsy management include the persistently high percentage of drug-refractoriness among patients, the absence of disease-modifying treatments, and its diagnosis and prognosis. To date, long-term video-electroencephalogram (EEG) recordings remain the gold standard for an epilepsy diagnosis. However, this is very costly, has low throughput, and in some instances has very limited availability. Therefore, much effort is put into the search for non-invasive diagnostic tests. Purinergic signalling, via extracellularly released adenosine triphosphate (ATP), is gaining increasing traction as a therapeutic strategy for epilepsy treatment which is supported by evidence from both experimental models and patients. This includes in particular the ionotropic P2X7 receptor. Besides that, other components from the ATPergic signalling cascade such as the metabotropic P2Y receptors (e.g., P2Y1 receptor) and ATP-release channels (e.g., pannexin-1), have also been shown to contribute to seizures and epilepsy. In addition to the therapeutic potential of purinergic signalling, emerging evidence has also shown its potential as a diagnostic tool. Following seizures and epilepsy, the concentration of purines in the blood and the expression of different compounds of the purinergic signalling cascade are significantly altered. Herein, this review will provide a detailed discussion of recent findings on the diagnostic potential of purinergic signalling for epilepsy management and the prospect of translating it for clinical application. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Lee NT, Ong LK, Gyawali P, Nassir CMNCM, Mustapha M, Nandurkar HH, et al.

Biomolecules, 2021 07 06;11(7).
PMID: 34356618 DOI: 10.3390/biom11070994

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.

Matched MeSH terms: Adenosine Triphosphate/metabolism*
Cellular and hormonal control in glycogen metabolism--recent advances

Thambyrajah V, Karunairatnam MC

Med J Malaya, 1972 Sep;27(1):33-9.
PMID: 4345646
Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Computational prediction of changes in brain metabolic fluxes during Parkinson's disease from mRNA expression

Supandi F, van Beek JHGM

PLoS One, 2018;13(9):e0203687.
PMID: 30208076 DOI: 10.1371/journal.pone.0203687

BACKGROUND: Parkinson's disease is a widespread neurodegenerative disorder which affects brain metabolism. Although changes in gene expression during disease are often measured, it is difficult to predict metabolic fluxes from gene expression data. Here we explore the hypothesis that changes in gene expression for enzymes tend to parallel flux changes in biochemical reaction pathways in the brain metabolic network. This hypothesis is the basis of a computational method to predict metabolic flux changes from post-mortem gene expression measurements in Parkinson's disease (PD) brain.
RESULTS: We use a network model of central metabolism and optimize the correspondence between relative changes in fluxes and in gene expression. To this end we apply the Least-squares with Equalities and Inequalities algorithm integrated with Flux Balance Analysis (Lsei-FBA). We predict for PD (1) decreases in glycolytic rate and oxygen consumption and an increase in lactate production in brain cortex that correspond with measurements (2) relative flux decreases in ATP synthesis, in the malate-aspartate shuttle and midway in the TCA cycle that are substantially larger than relative changes in glucose uptake in the substantia nigra, dopaminergic neurons and most other brain regions (3) shifts in redox shuttles between cytosol and mitochondria (4) in contrast to Alzheimer's disease: little activation of the gamma-aminobutyric acid shunt pathway in compensation for decreased alpha-ketoglutarate dehydrogenase activity (5) in the globus pallidus internus, metabolic fluxes are increased, reflecting increased functional activity.
CONCLUSION: Our method predicts metabolic changes from gene expression data that correspond in direction and order of magnitude with presently available experimental observations during Parkinson's disease, indicating that the hypothesis may be useful for some biochemical pathways. Lsei-FBA generates predictions of flux distributions in neurons and small brain regions for which accurate metabolic flux measurements are not yet possible.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Insensitivity of bacterial nucleic acid biosyntheses to a morphine-like narcotic

Wolfe AD, Hahn FE

Naturwissenschaften, 1975 Feb;62(2):99.
PMID: 1683
Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Glycoprotein IIb/IIIa and P2Y12 induction by oligochitosan accelerates platelet aggregation

Periayah MH, Halim AS, Yaacob NS, Saad AZ, Hussein AR, Rashid AH, et al.

Biomed Res Int, 2014;2014:653149.
PMID: 25247182 DOI: 10.1155/2014/653149

Platelet membrane receptor glycoprotein IIb/IIIa (gpiibiiia) is a receptor detected on platelets. Adenosine diphosphate (ADP) activates gpiibiiia and P2Y12, causing platelet aggregation and thrombus stabilization during blood loss. Chitosan biomaterials were found to promote surface induced hemostasis and were capable of activating blood coagulation cascades by enhancing platelet aggregation. Our current findings show that the activation of the gpiibiiia complex and the major ADP receptor P2Y12 is required for platelet aggregation to reach hemostasis following the adherence of various concentrations of chitosan biomaterials [7% N,O-carboxymethylchitosan (NO-CMC) with 0.45 mL collagen, 8% NO-CMC, oligochitosan (O-C), and oligochitosan 53 (O-C 53)]. We studied gpiibiiia and P2Y12 through flow cytometric analysis and western blotting techniques. The highest expression of gpiibiiia was observed with Lyostypt (74.3 ± 7.82%), followed by O-C (65.5 ± 7.17%). Lyostypt and O-C resulted in gpiibiiia expression increases of 29.2% and 13.9%, respectively, compared with blood alone. Western blot analysis revealed that only O-C 53 upregulated the expression of P2Y12 (1.12 ± 0.03-fold) compared with blood alone. Our findings suggest that the regulation of gpiibiiia and P2Y12 levels could be clinically useful to activate platelets to reach hemostasis. Further, we show that the novel oligochitosan is able to induce the increased expression of gpiibiiia and P2Y12, thus accelerating platelet aggregation in vitro.

Matched MeSH terms: Adenosine Triphosphate/metabolism*
Fulltext TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy

Sudi SB, Tanaka T, Oda S, Nishiyama K, Nishimura A, Sunggip C, et al.

Sci Rep, 2019 07 05;9(1):9785.
PMID: 31278358 DOI: 10.1038/s41598-019-46252-2

Myocardial atrophy, characterized by the decreases in size and contractility of cardiomyocytes, is caused by severe malnutrition and/or mechanical unloading. Extracellular adenosine 5'-triphosphate (ATP), known as a danger signal, is recognized to negatively regulate cell volume. However, it is obscure whether extracellular ATP contributes to cardiomyocyte atrophy. Here, we report that ATP induces atrophy of neonatal rat cardiomyocytes (NRCMs) without cell death through P2Y2 receptors. ATP led to overproduction of reactive oxygen species (ROS) through increased amount of NADPH oxidase (Nox) 2 proteins, due to increased physical interaction between Nox2 and canonical transient receptor potential 3 (TRPC3). This ATP-mediated formation of TRPC3-Nox2 complex was also pathophysiologically involved in nutritional deficiency-induced NRCM atrophy. Strikingly, knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, as well as ROS production and NRCM atrophy. Taken together, we propose that TRPC3-Nox2 axis, activated by extracellular ATP, is the key component that mediates nutritional deficiency-induced cardiomyocyte atrophy.

Matched MeSH terms: Adenosine Triphosphate/metabolism
The kinetic properties of the glutamate dehydrogenase of Teladorsagia circumcincta and their significance for the lifestyle of the parasite

Muhamad N, Simcock DC, Pedley KC, Simpson HV, Brown S

Comp Biochem Physiol B Biochem Mol Biol, 2011 Jun;159(2):71-7.
PMID: 21296180 DOI: 10.1016/j.cbpb.2011.01.008

Like other nematodes, both L(3) and adult Teladosagia circumcincta secrete or excrete NH(3)/NH(4)(+), but the reactions involved in the production are unclear. Glutamate dehydrogenase is a significant source NH(3)/NH(4)(+) in some species, but previous reports indicate that the enzyme is absent from L(3)Haemonchus contortus. We show that glutamate dehydrogenase was active in both L(3) and adult T. circumcincta. The apparent K(m)s of the L(3) enzyme differed from those of the adult enzyme, the most significant of these being the increase in the K(m) for NH(4)(+) from 18mM in L(3) to 49mM in adults. The apparent V(max) of the oxidative deamination reaction was greater than that of the reductive reaction in L(3), but this was reversed in adults. The activity of the oxidative reaction of the L(3) enzyme was not affected by adenine nucleotides, but that of the reductive reaction was stimulated significantly by either ADP or ATP. The L(3) enzyme was more active with NAD(+) than it was with NADP(+), although the activities supported by NADH and NADPH were similar at saturating concentrations. While the activity of the oxidative reaction was sufficient to account for the NH(3)/NH(4)(+) efflux we have previously reported, the reductive amination reaction was likely to be more active.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain

Hossain MZ, Bakri MM, Yahya F, Ando H, Unno S, Kitagawa J

Int J Mol Sci, 2019 Jan 27;20(3).
PMID: 30691193 DOI: 10.3390/ijms20030526

Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext C-phycocyanin confers protection against oxalate-mediated oxidative stress and mitochondrial dysfunctions in MDCK cells

Farooq SM, Boppana NB, Devarajan A, Asokan D, Sekaran SD, Shankar EM, et al.

PLoS One, 2014;9(4):e93056.
PMID: 24691130 DOI: 10.1371/journal.pone.0093056

Oxalate toxicity is mediated through generation of reactive oxygen species (ROS) via a process that is partly dependent on mitochondrial dysfunction. Here, we investigated whether C-phycocyanin (CP) could protect against oxidative stress-mediated intracellular damage triggered by oxalate in MDCK cells. DCFDA, a fluorescence-based probe and hexanoyl-lysine adduct (HEL), an oxidative stress marker were used to investigate the effect of CP on oxalate-induced ROS production and membrane lipid peroxidation (LPO). The role of CP against oxalate-induced oxidative stress was studied by the evaluation of mitochondrial membrane potential by JC1 fluorescein staining, quantification of ATP synthesis and stress-induced MAP kinases (JNK/SAPK and ERK1/2). Our results revealed that oxalate-induced cells show markedly increased ROS levels and HEL protein expression that were significantly decreased following pre-treatment with CP. Further, JC1 staining showed that CP pre-treatment conferred significant protection from mitochondrial membrane permeability and increased ATP production in CP-treated cells than oxalate-alone-treated cells. In addition, CP treated cells significantly decreased the expression of phosphorylated JNK/SAPK and ERK1/2 as compared to oxalate-alone-treated cells. We concluded that CP could be used as a potential free radical-scavenging therapeutic strategy against oxidative stress-associated diseases including urolithiasis.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids

Jubaidi FF, Zainalabidin S, Mariappan V, Budin SB

Int J Mol Sci, 2020 Aug 22;21(17).
PMID: 32842567 DOI: 10.3390/ijms21176043

As the powerhouse of the cells, mitochondria play a very important role in ensuring that cells continue to function. Mitochondrial dysfunction is one of the main factors contributing to the development of cardiomyopathy in diabetes mellitus. In early development of diabetic cardiomyopathy (DCM), patients present with myocardial fibrosis, dysfunctional remodeling and diastolic dysfunction, which later develop into systolic dysfunction and eventually heart failure. Cardiac mitochondrial dysfunction has been implicated in the development and progression of DCM. Thus, it is important to develop novel therapeutics in order to prevent the progression of DCM, especially by targeting mitochondrial dysfunction. To date, a number of studies have reported the potential of phenolic acids in exerting the cardioprotective effect by combating mitochondrial dysfunction, implicating its potential to be adopted in DCM therapies. Therefore, the aim of this review is to provide a concise overview of mitochondrial dysfunction in the development of DCM and the potential role of phenolic acids in combating cardiac mitochondrial dysfunction. Such information can be used for future development of phenolic acids as means of treating DCM by alleviating the cardiac mitochondrial dysfunction.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels

Kim Y, Griffin JM, Nor MNM, Zhang J, Freestone PS, Danesh-Meyer HV, et al.

Neurotherapeutics, 2017 Oct;14(4):1148-1165.
PMID: 28560708 DOI: 10.1007/s13311-017-0536-9

The cis benzopyran compound tonabersat (SB-220453) has previously been reported to inhibit connexin26 expression in the brain by attenuating the p38-mitogen-activated protein kinase pathway. We show here that tonabersat directly inhibits connexin43 hemichannel opening. Connexin43 hemichannels have been called "pathological pores" based upon their role in secondary lesion spread, edema, inflammation, and neuronal loss following central nervous system injuries, as well as in chronic inflammatory disease. Both connexin43 hemichannels and pannexin channels released adenosine triphosphate (ATP) during ischemia in an in vitro ischemia model, but only connexin43 hemichannels contributed to ATP release during reperfusion. Tonabersat inhibited connexin43 hemichannel-mediated ATP release during both ischemia and reperfusion phases, with direct channel block confirmed using electrophysiology. Tonabersat also reduced connexin43 gap junction coupling in vitro, but only at higher concentrations, with junctional plaques internalized and degraded via the lysosomal pathway. Systemic delivery of tonabersat in a rat bright-light retinal damage model (a model for dry age-related macular degeneration) resulted in significantly improved functional outcomes assessed using electroretinography. Tonabersat also prevented thinning of the retina, especially the outer nuclear layer and choroid, assessed using optical coherence tomography. We conclude that tonabersat, already given orally to over 1000 humans in clinical trials (as a potential treatment for, and prophylactic treatment of, migraine because it was thought to inhibit cortical spreading depression), is a connexin hemichannel inhibitor and may have the potential to be a novel treatment of central nervous system injury and chronic neuroinflammatory disease.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury

Dongworth RK, Mukherjee UA, Hall AR, Astin R, Ong SB, Yao Z, et al.

Cell Death Dis, 2014 Feb 27;5:e1082.
PMID: 24577080 DOI: 10.1038/cddis.2014.41

Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia-reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1(L166P) and DJ-1(Cys106A) mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Oxidised low density lipoprotein causes human macrophage cell death through oxidant generation and inhibition of key catabolic enzymes

Katouah H, Chen A, Othman I, Gieseg SP

Int J Biochem Cell Biol, 2015 Oct;67:34-42.
PMID: 26255116 DOI: 10.1016/j.biocel.2015.08.001

Oxidised low density lipoprotein (oxLDL) is thought to be a significant contributor to the death of macrophage cells observed in advanced atherosclerotic plaques. Using human-derived U937 cells we have examined the effect of cytotoxic oxLDL on oxidative stress and cellular catabolism. Within 3h of the addition of oxLDL, there was a rapid, concentration dependent rise in cellular reactive oxygen species followed by the loss of cellular GSH, and the enzyme activity of both glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aconitase. The loss of these catabolic enzymes was accompanied by the loss of cellular ATP and lower lactate generation. Addition of the macrophage antioxidant 7,8-dihydroneopterin inhibited the ROS generation, glutathione loss and catabolic inactivation. NOX was shown to be activated by oxLDL addition while apocynin inhibited the loss of GSH and cell viability. The data suggests that oxLDL triggers an excess of ROS production through NOX activation, and catabolic failure through thiol oxidation resulting in cell death.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study

Mahmod M, Pal N, Rayner J, Holloway C, Raman B, Dass S, et al.

J Cardiovasc Magn Reson, 2018 12 24;20(1):88.
PMID: 30580760 DOI: 10.1186/s12968-018-0511-6

BACKGROUND: Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity.
METHODS: Twenty seven HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent 1H-cardiovascular magnetic resonance spectroscopy (1H-CMRS) to measure MTG (lipid/water, %), 31P-CMRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking cardiovascular magnetic resonance (CMR) imaging for diastolic strain rate.
RESULTS: When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45 ± 0.25% vs. 0.64 ± 0.16%, p = 0.009) and reduced PCr/ATP (1.60 ± 0.09 vs. 2.00 ± 0.10, p = 0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO2 max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO2 max.
CONCLUSIONS: Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al.

Apoptosis, 2015 Oct;20(10):1373-87.
PMID: 26276035 DOI: 10.1007/s10495-015-1158-5

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

Matched MeSH terms: Adenosine Triphosphate/metabolism*
Fulltext Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats

Abdul Nasir NA, Agarwal R, Sheikh Abdul Kadir SH, Vasudevan S, Tripathy M, Iezhitsa I, et al.

PLoS One, 2017;12(3):e0174542.
PMID: 28350848 DOI: 10.1371/journal.pone.0174542

Cataract, a leading cause of blindness, is of special concern in diabetics as it occurs at earlier onset. Polyol accumulation and increased oxidative-nitrosative stress in cataractogenesis are associated with NFκB activation, iNOS expression, ATP depletion, loss of ATPase functions, calpain activation and proteolysis of soluble to insoluble proteins. Tocotrienol was previously shown to reduce lens oxidative stress and inhibit cataractogenesis in galactose-fed rats. In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Diabetic rats were treated with vehicle (DV) or tocotrienol (DT). A third group consists of normal, non-diabetic rats were treated with vehicle (NV). All treatments were given topically, bilaterally, twice daily for 8 weeks with weekly slit lamp monitoring. Subsequently, rats were euthanized and lenses were subjected to estimation of polyol accumulation, oxidative-nitrosative stress, NFκB activation, iNOS expression, ATP levels, ATPase activities, calpain activity and total protein levels. Cataract progression was delayed from the fifth week onwards in DT with lower mean of cataract stages compared to DV group (p<0.01) despite persistent hyperglycemia. Reduced cataractogenesis in DT group was accompanied with lower aldose reductase activity and sorbitol level compared to DV group (p<0.01). DT group also showed reduced NFκB activation, lower iNOS expression and reduced oxidative-nitrosative stress compared to DV group. Lenticular ATP and ATPase and calpain 2 activities in DT group were restored to normal. Consequently, soluble to insoluble protein ratio in DT group was higher compared to DV (p<0.05). In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative-nitrosative stress. These effects of tocotrienol invlove reduced NFκB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels.

Matched MeSH terms: Adenosine Triphosphate/metabolism

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