Beta-guanidinopropionic

MLN4924 is a selective neddylation inhibitor that has shown great potential in treating several cancer and metabolic diseases, including obesity. However, it remains largely unknown whether MLN4924 has similar effect on non-alcoholic liver disease (NAFLD), which is closely associated with metabolic disorders. Here, we investigated the role of MLN4924 in NAFLD treatment and the underlying mechanism of the action using primary hepatocytes stimulated with free fatty acid, as well as high-fat diet (HFD)-induced NAFLD mouse models...

Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4 months starting at 14 or 30 months of age...

Background: Stable angina pectoris (SAP) is one of the main types of coronary heart disease (CHD). To improve treatment outcomes, more effective biomarkers are needed. Currently, studies on the metabolic characteristics of SAP are lacking. Here, we explored the serum metabolomic profile of SAP and identified potential biomarkers and related pathways to assist the clinical diagnosis and treatment of SAP. Method: Thirty patients with SAP patients and 30 healthy controls (CON) without stenosis were selected for this study...

Background The adenosine triphosphate (ATP) regenerating enzyme creatine kinase (CK) is intimately involved in blood pressure generation. Consequently, the creatine transporter and CK inhibitor beta-guanidinopropionic acid (GPA) successfully reduced blood pressure in 16-week-old spontaneously hypertensive rats (SHR), but GPA may cause growth retardation in juvenile mammals. This report considers a serendipity observation of paradoxical growth increase after using GPA to prevent hypertension in three-week-old SHR...

Activation of AMP activated protein kinase (AMPK) signaling has been demonstrated to extend lifespan and improve healthspan across multiple species. This suggests pharmaceutical approaches to increase AMPK hold the potential to modify the aging process and promote healthy aging. Beta-guanidinopropionic acid (GPA) is a naturally occurring metabolite structurally similar to creatine. GPA is capable of activating AMPK signaling in mammalian models via competitive inhibition of cytosolic creatine kinase. A previous report suggested that dietary GPA supplementation increased lifespan in Drosophila through its effect on AMPK signaling and regulation of autophagy...

AMP-activated protein kinase (AMPK) is a central regulator of both lifespan and health across multiple model organisms. β-Guanidinopropionic acid (GPA) is an endogenous AMPK activator previously shown to improve metabolic function in young and obese mice. In this study, we tested whether age of administration significantly affects the physiological outcomes of GPA administration in mice. We report that intervention starting at 7-8 months (young) results in activation of AMPK signaling and a phenotype consisting of lower body mass, improved glucose control, enhanced exercise tolerance, and altered mitochondrial electron transport chain flux similar to previous reports...

We hypothesized that human variation in the activity of the ATP regenerating enzyme creatine kinase (CK) activity affects hypertension and cardiovascular disease risk. CK is tightly bound close to ATP-utilizing enzymes including Ca2+ -ATPase, myosin ATPase, and Na+ /K+ -ATPase, where it rapidly regenerates ATP from ADP, H+ , and phosphocreatine. Thus, relatively high CK was thought to enhance ATP-demanding processes including resistance artery contractility and sodium retention, and reduce ADP-dependent functions...

AIMS: Increasing evidence indicates that the ATP-generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure-lowering agent, we assessed the tolerability of a sub-therapeutic GPA dose in healthy men...

OBJECTIVE: Creatine kinase is reported to be a main predictor of blood pressure (BP) in the general population, with a strong correlation between resistance artery creatine kinase expression and clinical BP in humans. The enzyme rapidly regenerates ATP near cytoplasmic ATPases involved in pressor responses, including resistance artery contractility and renal sodium retention. Therefore, we assessed whether creatine kinase inhibition reduces BP. METHODS: We implemented the 'Animal Research: Reporting of In Vivo Experiments' guideline...

OBJECTIVE: There is increasing evidence that the ATP generating enzyme creatine kinase (CK) is involved in hypertension. The enzyme is central to the regeneration of ATP by using creatine phosphate and ADP, thereby forming creatine and ATP. We recently showed that beta-guanidinopropionic acid (GPA), a creatine analogue and competitive CK inhibitor, effectively and safely reduced blood pressure in the spontaneously hypertensive rat. This renders GPA to be potentially beneficial for blood pressure lowering...

BACKGROUND: Despite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population...

The supply of L-carnosine, a bioactive dipeptide of β-alanine and l-histidine, to the retina across the blood-retinal barrier (BRB) was studied. The in vivo and in vitro studies revealed low uptake activities for [(3)H]Gly-Sar, a representative dipeptide, suggesting that l-carnosine transport plays only a minor role at the BRB. The in vivo study using rats showed approximately 18- and 23-fold greater retinal uptake indexes (RUI) for [(3)H]β-alanine and [(3)H]l-histidine compared with that of a paracellular marker, respectively...

BACKGROUND: Creatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands...

Despite its degradation by ectonucleotidases, a low ATP concentration is present in the interstitial space; moreover, its level can markedly increase during various physiopathological conditions. ATP and uridine 5'-triphosphate (UTP) releases correlate with the occurrence of ventricular premature beats and ventricular tachycardia. ATP facilitates several voltage-dependent ionic currents including the L-type Ca(2+) current. More recently, ATP and UTP were also shown to induce a poor voltage-dependent, long-lasting current carried by the heterotetrameric transient receptor potential (TRP) channels TRPC3/7...

We investigated the ability of AMP-activated protein kinase (AMPK) to activate PPARgamma coactivator-1alpha (PGC-1alpha) in the brain, liver and brown adipose tissue (BAT) of the NLS-N171-82Q transgenic mouse model of Huntington's disease (HD). In the striatum of the HD mice, the baseline levels of PGC-1alpha, NRF1, NRF2, Tfam, COX-II, PPARdelta, CREB and ERRalpha mRNA and mitochondrial DNA (mtDNA), were significantly reduced. Administration of the creatine analog beta guanidinopropionic acid (GPA) reduced ATP and PCr levels and increased AMPK mRNA in both the cerebral cortex and striatum...

We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice...

GABA(C) receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, beta-alanine and taurine were evaluated at human rho(1)GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-guanidinopropionic acid (IC(50) = 2.2 microM) and guanidinoacetic acid (IC(50) = 5...

The orally administered creatine analogue beta-guanidinopropionic acid (beta-GPA) decreases plasma glucose levels by increasing the sensitivity to insulin. This effect is based on a beta-GPA induced expression of mRNA and total protein content of the insulin-responsive glucose transporter GLUT4. Although the oral availability of beta-GPA is well established, the underlying uptake mechanism has not yet been studied. We investigated whether the H(+)-coupled amino acid transporter PAT1, which is expressed in the apical membrane of intestinal cells, accepts guanidine derivatives as substrates...

Decreasing muscle phosphagen content through dietary administration of the creatine analog beta-guanidinopropionic acid (beta-GPA) improves skeletal muscle oxidative capacity and resistance to fatigue during aerobic exercise in rodents, similar to that observed with endurance training. Surprisingly, the effect of beta-GPA on muscle substrate metabolism has been relatively unexamined, with only a few reports of increased muscle GLUT4 content and insulin-stimulated glucose uptake/clearance in rodent muscle. The effect of chronically decreasing muscle phophagen content on muscle fatty acid (FA) metabolism (transport, oxidation, esterification) is virtually unknown...

BACKGROUND: The failing heart is characterized by disturbed myocardial energy metabolism and creatine depletion. The aims of this study were to evaluate in vivo the effects of creatine (Cr) depletion on 1) left ventricular (LV) function, morphology, and lipid metabolism and 2) to test whether functional, morphologic, and metabolic disturbances induced by Cr depletion are reversible. METHODS AND RESULTS: Male Balb/c mice approximately 20 g were used. Two groups were studied: the mice treated with creatine analogue beta-guanidinopropionic acid (BGP) (n = 30) and controls (n = 30)...