Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.

• Klíčová slova
• Amino acid, Biosynthesis, Cancer, Leukemia, Malate-aspartate shuttle, Respiratory chain, Tumor microenvironment,
• MeSH
• kyselina asparagová * metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí * MeSH
• nádory * metabolismus   patologie   MeSH
• proliferace buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• kyselina asparagová * MeSH

OBJECTIVE: Many patients with long COVID experience neurological and psychological symptoms. Signal abnormalities on MR images in the corpus callosum have been reported. Knowledge about the metabolic profile in the splenium of the corpus callosum (CCS) may contribute to a better understanding of the pathophysiology of long COVID. MATERIALS AND METHODS: Eighty-one subjects underwent proton MR spectroscopy examination. The metabolic concentrations of total N-acetylaspartate (NAA), choline-containing compounds (Cho), total creatine (Cr), myo-inositol (mI), and NAA/Cho in the CCS were statistically compared in the group of patients containing 58 subjects with positive IgG COVID-19 antibodies or positive SARS-CoV-2 qPCR test at least two months before the MR and the group of healthy controls containing 23 subjects with negative IgG antibodies. RESULTS: An age-dependent effect of SARS-CoV-2 on Cho concentrations in the CCS has been observed. Considering the subjective threshold of age = 40 years, older patients showed significantly increased Cho concentrations in the CCS than older healthy controls (p = 0.02). NAA, Cr, and mI were unchanged. All metabolite concentrations in the CCS of younger post-COVID-19 patients remained unaffected by SARS-CoV-2. Cho did not show any difference between symptomatic and asymptomatic patients (p = 0.91). DISCUSSION: Our results suggest that SARS-CoV-2 disproportionately increases Cho concentration in the CCS among older post-COVID-19 patients compared to younger ones. The observed changes in Cho may be related to the microstructural reorganization in the CCS also reported in diffusion measurements rather than increased membrane turnover. These changes do not seem to be related to neuropsychological problems of the post-COVID-19 patients. Further metabolic studies are recommended to confirm these observations.

• Klíčová slova
• COVID-19, Metabolism, Proton MR spectroscopy, The splenium of the corpus callosum,
• MeSH
• cholin * metabolismus   MeSH
• corpus callosum * diagnostické zobrazování   metabolismus   MeSH
• COVID-19 * diagnostické zobrazování   metabolismus   MeSH
• dospělí MeSH
• inositol metabolismus   MeSH
• kreatin * metabolismus   MeSH
• kyselina asparagová * analogy a deriváty   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• protonová magnetická rezonanční spektroskopie * metody   MeSH
• SARS-CoV-2 * MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholin * MeSH
• inositol MeSH
• kreatin * MeSH
• kyselina asparagová * MeSH
• N-acetylaspartate MeSH Prohlížeč

AIM: Patients with multiple brain metastases (BM) benefit from hippocampal-avoiding whole brain radiotherapy (HA-WBRT), the challenging and less available form of WBRT. This study explores potential of pre-radiotherapy (pre-RT) hippocampal magnetic resonance spectroscopy (MRS) measuring hippocampal neuronal density as an imaging surrogate and predictive tool for assessing neurocognitive functions (NCF). METHODS: 43 BM patients underwent pre-RT hippocampal MRS. N-acetyl aspartate (NAA) concentration, a marker for neuronal density (weighted by creatine (Cr) and choline (Cho) concentrations), and neurocognitive function (NCF) tests (HVLT and BVMT) performed by certified psychologists were evaluated. Clinical variables and NAA concentrations were correlated with pre-RT NCFs. RESULTS: HVLT and BVMT subtests showed pre-RT deterioration except for BVMT recognition. Significantly better NCFs were observed in women in HVLT subsets. Significantly higher NAA/Cr + Cho was measured in women (median 0.63 vs. 0.55; P=0.048) in the left hippocampus (no difference in the right hippocampus). In men, a positive correlation (0.51, P=0.018) between total brain volume and HVLT-TR, between left hippocampal NAA/Cr + Cho and HVLT-R (0.45, P=0.063), and between right hippocampal NAA/Cr + Cho and BVMT-recognition (0.49, P=0.054) was observed. In women, a borderline significant negative correlation was observed between left hippocampal NAA/Cr + Cho and BVMT-TR (-0.43, P=0.076) and between right NAA/Cr + Cho and HVLT-DR (-0.42, P=0.051). CONCLUSION: Borderline statistically significant correlations were observed with speculative interpretation underlying the challenges of hippocampal MRS as a surrogate for neurocognitive impairment. Further studies need to be done to ascertain the opportunities for imaging predictors of benefit from memory sparing radiotherapy.

• Klíčová slova
• MR spectroscopy, hippocampus, neurocognitive function, radiotherapy,
• MeSH
• cholin metabolismus   MeSH
• dospělí MeSH
• hipokampus * diagnostické zobrazování   patologie   MeSH
• kognitivní dysfunkce etiologie   MeSH
• kraniální ozáření škodlivé účinky   MeSH
• kreatin metabolismus   MeSH
• kyselina asparagová analogy a deriváty   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie * metody   MeSH
• nádory mozku * radioterapie   sekundární   MeSH
• neuropsychologické testy MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholin MeSH
• kreatin MeSH
• kyselina asparagová MeSH
• N-acetylaspartate MeSH Prohlížeč

Major depressive disorder (MDD) is underlined by neurochemical changes in the brain. Proton magnetic resonance spectroscopy (1H MRS) is a useful tool for their examination as it provides information about the levels of metabolites. This review summarises the current knowledge of 1H MRS findings from rodent models of MDD, assesses the results from both a biological and a technical perspective, and identifies the main sources of bias. From a technical point of view, bias-introducing factors are the diversity of the measured volumes and their positioning in the brain, the data processing, and the metabolite concentration expression. The biological variables are strain, sex, and species, as well as the model itself, and in vivo vs. ex vivo exploration. This review identified some consistency in the 1H MRS findings in the models of MDD: lower levels of glutamine, glutamate + glutamine, and higher levels of myo-inositol and taurine in most of the brain regions of MDD models. This may suggest changes in regional metabolism, neuronal dysregulation, inflammation, and a compensatory effect reaction in the MDD rodent models.

• Klíčová slova
• Animal models, Depression, Metabolites, Proton magnetic resonance spectroscopy,
• MeSH
• deprese MeSH
• depresivní porucha unipolární * metabolismus   MeSH
• glutamin * metabolismus   MeSH
• hlodavci metabolismus   MeSH
• kyselina asparagová metabolismus   MeSH
• kyselina glutamová metabolismus   MeSH
• mozek metabolismus   MeSH
• protonová magnetická rezonanční spektroskopie metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• glutamin * MeSH
• kyselina asparagová MeSH
• kyselina glutamová MeSH

BACKGROUND: The main aim of the present study is to determine the role of metabolites observed using proton magnetic resonance spectroscopy (1H-MRS) in obsessive-compulsive disorder (OCD). As the literature describing biochemical changes in OCD yields conflicting results, we focused on accurate metabolite quantification of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline-containing compounds (tCh), and myo-inositol (mI) in the anterior cingulate cortex (ACC) to capture the small metabolic changes between OCD patients and controls and between OCD patients with and without medication. METHODS: In total 46 patients with OCD and 46 healthy controls (HC) matched for age and sex were included in the study. The severity of symptoms in the OCD was evaluated on the day of magnetic resonance imaging (MRI) using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Subjects underwent 1H-MRS from the pregenual ACC (pgACC) region to calculate concentrations of tNAA, tCr, tCho, and mI. Twenty-eight OCD and 28 HC subjects were included in the statistical analysis. We compared differences between groups for all selected metabolites and in OCD patients we analyzed the relationship between metabolite levels and symptom severity, medication status, age, and the duration of illness. RESULTS: Significant decreases in tCr (U = 253.00, p = 0.022) and mI (U = 197.00, p = 0.001) in the pgACC were observed in the OCD group. No statistically significant differences were found in tNAA and tCho levels; however, tCho revealed a trend towards lower concentrations in OCD patients (U = 278.00, p = 0.062). Metabolic concentrations showed no significant correlations with the age and duration of illness. The correlation statistics found a significant negative correlation between tCr levels and YBOCS compulsions subscale (cor = -0.380, p = 0.046). tCho and YBOCS compulsions subscale showed a trend towards a negative correlation (cor = -0.351, p = 0.067). Analysis of subgroups with or without medication showed no differences. CONCLUSIONS: Patients with OCD present metabolic disruption in the pgACC. The decrease in tCr shows an important relationship with OCD symptomatology. tCr as a marker of cerebral bioenergetics may also be considered as a biomarker of the severity of compulsions. The study failed to prove that metabolic changes correlate with the medication status or the duration of illness. It seems that a disruption in the balance between these metabolites and their transmission may play a role in the pathophysiology of OCD.

• Klíčová slova
• Choline-containing compounds, Creatine, Magnetic resonance spectroscopy, Myo-inositol, N-acetyl aspartate, Obsessive-compulsive disorder,
• MeSH
• cingulární gyrus diagnostické zobrazování   metabolismus   MeSH
• glutamin * metabolismus   MeSH
• inositol metabolismus   terapeutické užití   MeSH
• kreatin metabolismus   terapeutické užití   MeSH
• kyselina asparagová metabolismus   terapeutické užití   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• obsedantně kompulzivní porucha * diagnóza   MeSH
• protonová magnetická rezonanční spektroskopie metody   MeSH
• receptory antigenů T-buněk metabolismus   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glutamin * MeSH
• inositol MeSH
• kreatin MeSH
• kyselina asparagová MeSH
• receptory antigenů T-buněk MeSH

Gluconeogenesis, a pathway for glucose synthesis from non-carbohydrate substances, begins with the synthesis of oxaloacetate (OA) from pyruvate and intermediates of citric acid cycle in hepatocyte mitochondria. The traditional view is that OA does not cross the mitochondrial membrane and must be shuttled to the cytosol, where most enzymes involved in gluconeogenesis are compartmentalized, in the form of malate. Thus, the possibility of transporting OA in the form of aspartate has been ignored. In the article is shown that malate supply to the cytosol increases only when fatty acid oxidation in the liver is activated, such as during starvation or untreated diabetes. Alternatively, aspartate synthesized from OA by mitochondrial aspartate aminotransferase (AST) is transported to the cytosol in exchange for glutamate via the aspartate-glutamate carrier 2 (AGC2). If the main substrate for gluconeogenesis is an amino acid, aspartate is converted to OA via urea cycle, therefore, ammonia detoxification and gluconeogenesis are simultaneously activated. If the main substrate is lactate, OA is synthesized by cytosolic AST, glutamate is transported to the mitochondria through AGC2, and nitrogen is not lost. It is concluded that, compared to malate, aspartate is a more suitable form of OA transport from the mitochondria for gluconeogenesis.

• Klíčová slova
• AGC2, Citrin, Mitochondrial carriers, Oxaloacetate, Urea cycle,
• MeSH
• glukoneogeneze * MeSH
• glutamáty metabolismus   MeSH
• kyselina asparagová * metabolismus   MeSH
• kyselina mléčná MeSH
• kyselina pyrohroznová MeSH
• maláty MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• glutamáty MeSH
• kyselina asparagová * MeSH
• kyselina mléčná MeSH
• kyselina pyrohroznová MeSH
• maláty MeSH
• malic acid MeSH Prohlížeč

Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into the cytosol in exchange for glutamate. The AGC2 is the main component of the malate-aspartate shuttle (MAS) that ensures indirect transport of NADH produced in the cytosol during glycolysis, lactate oxidation to pyruvate, and ethanol oxidation to acetaldehyde into mitochondria. Through MAS, AGC2 is necessary to maintain intracellular redox balance, mitochondrial respiration, and ATP synthesis. Through elevated cytosolic Ca2+ level, the AGC2 is stimulated by catecholamines and glucagon during starvation, exercise, and muscle wasting disorders. In these conditions, AGC2 increases aspartate input to the urea cycle, where aspartate is a source of one of two nitrogen atoms in the urea molecule (the other is ammonia), and a substrate for the synthesis of fumarate that is gradually converted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for the synthesis of asparagine, nucleotides, and proteins. It is concluded that AGC2 plays a fundamental role in the compartmentalization of aspartate and glutamate metabolism and linkage of the reactions of MAS, glycolysis, gluconeogenesis, amino acid catabolism, urea cycle, protein synthesis, and cell proliferation. Targeting of AGC genes may represent a new therapeutic strategy to fight cancer. [BMB Reports 2023; 56(7): 385-391].

• MeSH
• glukosa * metabolismus   MeSH
• játra metabolismus   MeSH
• kyselina asparagová * metabolismus   MeSH
• kyselina glutamová metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• aspartate-glutamate carrier MeSH Prohlížeč
• citrin MeSH Prohlížeč
• glukosa * MeSH
• kyselina asparagová * MeSH
• kyselina glutamová MeSH

OBJECTIVES: Pilot study validating the animal model of depression - the bilateral olfactory bulbectomy in rats - by two nuclear magnetic resonance methods, indirectly detecting the metabolic state of the brain. Furthermore, the study focussed on potential differences in brain laterality. METHODS: Arterial spin labelling assessed cerebral brain flow in prefrontal, sensorimotor, and piriform cortices, nucleus accumbens, hippocampus, thalamus, circle of Willis, and whole brain. Proton magnetic resonance spectroscopy provided information about relative metabolite concentrations in the cortex and hippocampus. RESULTS: Arterial spin labelling found no differences in cerebral perfusion in the group comparison but revealed lateralisation in the thalamus of the control group and the sensorimotor cortex of the bulbectomized rats. Lower Cho/tCr and Cho/NAA levels were found in the right hippocampus in bulbectomized rats. The differences in lateralisation were shown in the hippocampus: mI/tCr in the control group, Cho/NAA, NAA/tCr, Tau/tCr in the model group, and in the cortex: NAA/tCr, mI/tCr in the control group. CONCLUSION: Olfactory bulbectomy affects the neuronal and biochemical profile of the rat brain laterally and, as a model of depression, was validated by two nuclear magnetic resonance methods.

• Klíčová slova
• Arterial spin labelling, depression, magnetic resonance spectroscopy, olfactory bulbectomy, rats,
• MeSH
• cholin metabolismus   MeSH
• kreatin metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina asparagová metabolismus   MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• magnetická rezonanční tomografie * MeSH
• mozek * patologie   MeSH
• pilotní projekty MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholin MeSH
• kreatin MeSH
• kyselina asparagová MeSH
• receptory antigenů T-buněk MeSH

Mitochondria and mitochondrial proteins represent a group of promising pharmacological target candidates in the search of new molecular targets and drugs to counteract the onset of hypertension and more in general cardiovascular diseases (CVDs). Indeed, several mitochondrial pathways result impaired in CVDs, showing ATP depletion and ROS production as common traits of cardiac tissue degeneration. Thus, targeting mitochondrial dysfunction in cardiomyocytes can represent a successful strategy to prevent heart failure. In this context, the identification of new pharmacological targets among mitochondrial proteins paves the way for the design of new selective drugs. Thanks to the advances in omics approaches, to a greater availability of mitochondrial crystallized protein structures and to the development of new computational approaches for protein 3D-modelling and drug design, it is now possible to investigate in detail impaired mitochondrial pathways in CVDs. Furthermore, it is possible to design new powerful drugs able to hit the selected pharmacological targets in a highly selective way to rescue mitochondrial dysfunction and prevent cardiac tissue degeneration. The role of mitochondrial dysfunction in the onset of CVDs appears increasingly evident, as reflected by the impairment of proteins involved in lipid peroxidation, mitochondrial dynamics, respiratory chain complexes, and membrane polarization maintenance in CVD patients. Conversely, little is known about proteins responsible for the cross-talk between mitochondria and cytoplasm in cardiomyocytes. Mitochondrial transporters of the SLC25A family, in particular, are responsible for the translocation of nucleotides (e.g., ATP), amino acids (e.g., aspartate, glutamate, ornithine), organic acids (e.g. malate and 2-oxoglutarate), and other cofactors (e.g., inorganic phosphate, NAD+, FAD, carnitine, CoA derivatives) between the mitochondrial and cytosolic compartments. Thus, mitochondrial transporters play a key role in the mitochondria-cytosol cross-talk by leading metabolic pathways such as the malate/aspartate shuttle, the carnitine shuttle, the ATP export from mitochondria, and the regulation of permeability transition pore opening. Since all these pathways are crucial for maintaining healthy cardiomyocytes, mitochondrial carriers emerge as an interesting class of new possible pharmacological targets for CVD treatments.

• Klíčová slova
• Aquaporin, Cardiolipin, Cardiovascular diseases, Drug-Repurposing, Genomics, Hypertension, Ischemia reperfusion injury, Metabolomics, Mitochondrial carriers, Mitochondrial diseases, Mitochondrial dynamics, Mitochondrial dysfunction, Mitochondrial impairment, Mitochondrial metabolite transport system, Mitochondrial permeability transition pore, Mitochondrial pharmacological targets, Mitochondrial pyruvate carrier, Mitochondrial targets for CVD treatments, Molecular modeling of mitochondrial proteins, Respiratory chain, Transcriptomics, Voltage-dependent anion channels,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• hypertenze * metabolismus   MeSH
• kardiovaskulární nemoci * farmakoterapie   metabolismus   MeSH
• kyselina asparagová metabolismus   MeSH
• lidé MeSH
• maláty metabolismus   MeSH
• mitochondriální proteiny metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• reperfuzní poškození * metabolismus   MeSH
• transportní proteiny mitochondriální membrány metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adenosintrifosfát MeSH
• kyselina asparagová MeSH
• maláty MeSH
• mitochondriální proteiny MeSH
• transportní proteiny mitochondriální membrány MeSH

Apolipoprotein J (clusterin) is a component of high-density lipoproteins, the high level of which is reversely correlated with the risk of coronary heart disease. In addition, it exerts anti-inflammatory and anti-apoptotic effects on endothelial cells and inhibits smooth muscle cell migration and proliferation, indicating that it may play a protective role in cardiovascular disease. However, the exact mechanisms by which this occurs remain unclear. This study aimed to clarify these underlying protective mechanisms by researching the inhibitory effects of apolipoprotein J via the NOD-like receptor protein 3 pathway on the inflammation induced by cholesterol crystals in THP‑1 macrophages. In culture, THP-1 macrophages were infected with adenoviral vectors containing apolipoprotein J genes and subsequently treated with cholesterol crystals. The inflammatory cytokines interleukin‑1β, interleukin 18 and tumour necrosis factor α were quantitatively measured with ELISA kits. NOD-like receptor protein 3, cysteinyl aspartate specific proteinase 1 and interleukin 1β were evaluated by Western blot and PCR analysis. As a result, apolipoprotein J expression was found to remarkably decrease the levels of inflammatory cytokines, including tumour necrosis factor α, interleukin 18 and interleukin 1β, secreted by THP‑1 macrophages. It was also found capable of inhibiting the levels of NOD-like receptor protein 3, cysteinyl aspartate-specific proteinase 1 and interleukin 1β both at the protein and mRNA levels. In the current study, we revealed that over-expression of apolipoprotein J attenuated the inflammation induced by cholesterol crystals through inhibition of the NOD-like receptor protein 3 inflammasome pathway.

• MeSH
• cholesterol metabolismus   MeSH
• cytokiny metabolismus   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• inflamasomy * metabolismus   farmakologie   MeSH
• interleukin-18 metabolismus   MeSH
• interleukin-1beta metabolismus   MeSH
• klusterin metabolismus   farmakologie   MeSH
• kyselina asparagová metabolismus   farmakologie   MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• proteasy metabolismus   farmakologie   MeSH
• protein NLRP3 * metabolismus   MeSH
• TNF-alfa metabolismus   MeSH
• zánět patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• cytokiny MeSH
• inflamasomy * MeSH
• interleukin-18 MeSH
• interleukin-1beta MeSH
• klusterin MeSH
• kyselina asparagová MeSH
• NLRP3 protein, human MeSH Prohlížeč
• proteasy MeSH
• protein NLRP3 * MeSH
• TNF-alfa MeSH