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1.
Life Sci Alliance ; 5(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36114003

RESUMO

Solute carrier (SLC) transporters control fluxes of nutrients and metabolites across membranes and thereby represent a critical interface between the microenvironment and cellular and subcellular metabolism. Because of substantial functional overlap, the interplay and relative contributions of SLCs in response to environmental stresses remain poorly elucidated. To infer functional relationships between SLCs and metabolites, we developed a strategy to identify SLCs able to sustain cell viability and proliferation under growth-limiting concentrations of essential nutrients. One-by-one depletion of 13 amino acids required for cell proliferation enabled gain-of-function genetic screens using a SLC-focused CRISPR/Cas9-based transcriptional activation approach to uncover transporters relieving cells from growth-limiting metabolic bottlenecks. Among the transporters identified, we characterized the cationic amino acid transporter SLC7A3 as a gene that, when up-regulated, overcame low availability of arginine and lysine by increasing their uptake, whereas SLC7A5 was able to sustain cellular fitness upon deprivation of several neutral amino acids. Moreover, we identified metabolic compensation mediated by the glutamate/aspartate transporters SLC1A2 and SLC1A3 under glutamine-limiting conditions. Overall, this gain-of-function approach using human cells uncovered functional transporter-nutrient relationships and revealed that transport activity up-regulation may be sufficient to overcome environmental metabolic restrictions.


Assuntos
Glutamina , Transportador 1 de Aminoácidos Neutros Grandes , Sistemas de Transporte de Aminoácidos Básicos/genética , Aminoácidos/metabolismo , Arginina , Ácido Aspártico , Mutação com Ganho de Função , Glutamatos , Humanos , Lisina , Proteínas de Membrana Transportadoras/metabolismo , Nutrientes
2.
Expert Rev Clin Pharmacol ; 15(9): 1067-1080, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36062480

RESUMO

INTRODUCTION: Ashwagandha (ASW) is the extract of the plant Withania somnifera. It is widely used in complementary, alternative, and integrative medicine (CAIM) but is little discussed in mainstream modern medical literature. AREAS COVERED: We performed a review of potential pharmacotherapeutic properties of ASW. Studies were sourced from relevant online and offline databases. In animal models, ASW displays antioxidant activity. It has GABAergic and other neurotransmitter modulatory effects. It reduces apoptosis and promotes synaptic plasticity. It improves cognition and reverses induced cognitive deficits. It attenuates indices of stress. In human subjects, ASW enhances adaptogenesis in healthy adults. It modestly benefits generalized anxiety disorder and obsessive-compulsive disorder, and symptom severity in schizophrenia, substance use disorders, and attention deficit hyperactivity disorder. It improves sleep quality. EXPERT OPINION: ASW may confer modest benefit in certain neuropsychiatric conditions. Its benefits may arise from induction of neuroplasticity, antioxidant and anti-inflammatory effects, and modulation of GABA and glutamate, as well as other neurotransmitters. The antioxidant and anti-inflammatory actions may also benefit neurodegenerative states. Reports of clinical benefit with ASW must be interpreted with caution, given the paucity of randomized clinical trials (RCTs). Greater methodological rigor is necessary before clinical recommendations on ASW can be confidently made.


ASW is an extract of the Indian winter review and meta-analysis of four RCTs reported scientific studies on the use of ASW in animal and human subjects in order to identify potential clinical uses in modern medicine.Our review finds that ASW has antioxidant and anti-inflammatory action. It also modulates the effects of several neurotransmitters in the brain. It attenuates laboratory and clinical indices of stress. These mechanisms may benefit mental illnesses such as anxiety, depression, obsessive-compulsive disorder, schizophrenia, attention deficit hyperactivity disorder, and addictive disorders. ASW improves exercise capacity in healthy adults. It also appears to improve sleep quality. In addition, ASW may also improve cognitive functioning post-brain injury and in those at risk of dementia. There is evidence from animal models that ASW may also be of benefit in cancer, stroke, and induced organ damage.These studies, while suggesting a wide range of potential clinical applications for ASW, must be viewed with caution because the clinical data are based on small numbers of patients treated for a relatively short period of time. Many clinical trials that found benefits with ASW were one-off studies that have not been replicated. Larger and more methodologically stringent clinical trials are required before ASW can be confidently recommended for clinical use. Because ASW is a herbal extract and because the efficacy of its many constituents is not known, it is not possible to generalize conclusions to all extracts, whether standardized or not.


Assuntos
Neuropsiquiatria , Withania , Adulto , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Glutamatos , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ácido gama-Aminobutírico
3.
ACS Chem Neurosci ; 13(18): 2681-2698, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36074422

RESUMO

As a contribution to the development of new dual/multifunctional drugs, a novel therapeutical scaffold merging key structural features from memantine and M30D was designed, synthesized, and explored for its AChE/BuChE inhibitory activity and neuroprotective effects. All synthetized hybrids were not able to inhibit AChE, but most of them exhibit inhibition with high selectivity toward butyrylcholinesterase (BuChE). Notably, among the tested compounds, amantadine/M30D hybrids with six, seven, nine, and twelve methylene groups in the spacer (5d, 5e, 5f, and 5g) not only highlighted having the best potency and selective butyrylcholinesterase inhibition greater than 83% but also, particularly 5e and 5d, elicited considerable neuroprotection when evaluated in pretreatment conditions, by reducing injury effects caused by glutamate with maximum protection reached about 47.82 ± 0.81% (5e) and 42 ± 2.20% (5d) in comparison with memantine (37.27 ± 2.69%). Likewise, we chose 5e as the hit compound, which in a glutamate excitotoxity coculture model prevented astroglia reactivity and neuronal death, as well as a 91% restoration of calcium levels and an increasing ATP level in both pre-/post-treatments of 61.48 ± 4.60 and 45.16 ± 10.55%, respectively. Regarding docking studies, a blockade of the NMDA channel pore by 5e would explain its neuroprotective response. Finally, the hit compound 5e exhibited in vitro blood-brain barrier (BBB) permeability and human plasma stability, as well as an optimal in silico neuropharmacokinetic profile. From a therapeutic perspective, merging key pharmacophoric features from memantine and M30D provides a new medicinal scaffold with dual-/multifunctional properties and human plasma stability for the future development of potential drugs for treating AD.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Trifosfato de Adenosina , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase , Cálcio , Inibidores da Colinesterase/uso terapêutico , Glutamatos , Humanos , Memantina/farmacologia , Memantina/uso terapêutico , Simulação de Acoplamento Molecular , N-Metilaspartato , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 70(37): 11727-11737, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36084346

RESUMO

Amadori rearrangement products (ARPs) derived from the Maillard reaction between theanine and glucose (ARP 1), as well as pyroglutamic acid and glucose (ARP 2), were identified by liquid chromatograph tandem mass spectroscopy methods. The effects of initial reactant ratio, temperature, pH, and heating time on ARP generation were analyzed. The formation of both ARPs was most favored under 100 °C, while an alkaline environment slightly promoted the generation of ARP 1 and acidic conditions contributed more to ARP 2 formation. The decomposition of ARP 1 was suggested to be the predominant formation mechanism of ARP 2. Preparation, purification, and structure identification of ARP 1 were conducted, with its structure confirmed as 1-deoxy-1-l-theanino-d-fructose. The contents of ARP 1 in green, black, dark, white, yellow, and Oolong teas were quantitatively determined, of which black teas contained the highest levels of ARP 1, possibly due to the high glucose content and processing techniques.


Assuntos
Glucose , Ácido Pirrolidonocarboxílico , Frutose , Glucose/química , Glutamatos , Reação de Maillard , Chá
5.
Chem Res Toxicol ; 35(9): 1570-1578, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36048166

RESUMO

Exposure to organophosphorus pesticides (OP) can have chronic adverse effects that are independent of inhibition of acetylcholinesterase, the classic target for acute OP toxicity. In pure proteins, the organophosphorus pesticide chlorpyrifos oxon induces a cross-link between lysine and glutamate (or aspartate) with loss of water. Tubulin is particularly sensitive to OP-induced cross-linking. Our goal was to explore OP-induced cross-linking in a complex protein sample, MAP-rich tubulin from Sus scrofa and to test 8 OP for their capacity to promote isopeptide cross-linking. We treated 100 µg of MAP-rich tubulin with 100 µM chlorpyrifos, chlorpyrifos oxon, methamidophos, paraoxon, diazinon, diazoxon, monocrotophos, or dichlorvos. Each sample was separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and stained with Coomassie blue. Five gel slices (at about 30, 50, 150, and 300 kDa, and the top of the separating gel) were removed from the lanes for each of the eight OP samples and from untreated control lanes. These gel slices were subjected to in-gel trypsin digestion. MSMS fragmentation spectra of the tryptic peptides were examined for isopeptide cross-links. Sixteen spectra yielded convincing evidence for isopeptide cross-linked peptides. Ten were from the chlorpyrifos oxon reaction, 1 from dichlorvos, 1 from paraoxon, 1 from diazinon, and 3 from diazoxon. It was concluded that catalysis of protein cross-linking is a general property of organophosphorus pesticides and pesticide metabolites. Data are available via ProteomeXchange with identifier PXD034529.


Assuntos
Clorpirifos , Monocrotofós , Praguicidas , Acetilcolinesterase/metabolismo , Ácido Aspártico , Clorpirifos/análogos & derivados , Clorpirifos/química , Diazinon , Diclorvós , Glutamatos , Lisina/química , Compostos Organofosforados/química , Paraoxon/metabolismo , Peptídeos/química , Praguicidas/toxicidade , Dodecilsulfato de Sódio , Tripsina , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Água
6.
J Pharm Biomed Anal ; 220: 114986, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-35963019

RESUMO

Human immunodeficiency viral (HIV) infection and long-term use of combination antiretroviral therapy (cART) have both been associated with the development of metabolic and immunological complications. Despite having many markers for HIV disease progression, the reliability of these markers remains debatable and most of these cannot be used as valid markers for treatment response. As such, it remains important to discover and develop biological markers, which will aid in monitoring disease progression, treatment response and the diagnoses of HIV-related metabolic disorders. Previous HIV-metabonomics studies unravelled the ability to detect and measure potential biological markers of HIV disease progression and treatment response. Several significantly differing metabolites were identified, however, only a small number of studies have investigated the link of specific metabolic disorders to an exact antiretroviral regimen. Here, an NMR-based untargeted metabonomic approach was used to profile metabolic changes in the sera of 24 HIV+ cART+ individuals receiving Zidovudine-based combination antiretroviral therapy compared to their 15 HIV+ ART- and 38 HIV- counterparts. Chemometric analysis identified significant differences in metabolic features related to glutamine, glutamate, glutathione, glucose and arginine. Pathway analysis also revealed the glutamine and glutamate metabolism pathway as the most significantly altered pathway between the HIV+ cART+ and HIV+ cART- group. Findings from this study further confirm the reliability of NMR-based metabonomics in HIV biomarker discovery. In addition, this study contributes to our understandings of the metabolic effect of antiretroviral therapy.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Arginina/metabolismo , Biomarcadores , Progressão da Doença , Glucose , Glutamatos , Glutamina/metabolismo , Glutationa/metabolismo , Humanos , Estresse Oxidativo , Reprodutibilidade dos Testes , Zidovudina/uso terapêutico
7.
Pharmacol Biochem Behav ; 219: 173446, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35987339

RESUMO

Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.


Assuntos
Ansiolíticos , Doença de Parkinson , Receptores de Glutamato Metabotrópico , Esquizofrenia , Ansiolíticos/uso terapêutico , Glutamatos/uso terapêutico , Humanos , Esquizofrenia/tratamento farmacológico
8.
Chem Biodivers ; 19(9): e202200230, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35970767

RESUMO

Three freshwater microalgae (Spirogyra sp., Cosmarium sp., and Cosmarium blytii) collected from several locations in Gran Canaria have been studied to explore their potential as a novel source of bioactive compounds for biotechnological applications. Soluble carbohydrates were quantified after extraction with 3 M HCl at 100 °C, ranging from 35.8 to 43.3 %, and with water at room temperature, ranging from 19 to 22.8 %. Amino acids glutamic acid, proline and aspartic acid were quantified by RP-HPLC. Glutamic acid was the most abundant, ranging from 12.2 to 3.63 mg g-1 of dry biomass. Cosmarium blytii was the richest sample in amino acids (24.02 mg g-1 of dry weight). In addition, Cosmarium blytii and Spyrogira sp. exhibited higher radical scavenging activity (RSA) against 1,1-diphenyl-2-picrylhydrazyl (DPPH) than that of the synthetic antioxidant butylhydroxytoluene (BHT), commonly used as food additive. These results show a great potential of these microalgae for exploitation in the food, feed and pharmaceutical industries.


Assuntos
Microalgas , Antioxidantes/química , Ácido Aspártico/metabolismo , Hidroxitolueno Butilado , Carboidratos , Aditivos Alimentares/metabolismo , Alimento Funcional , Glutamatos/metabolismo , Microalgas/química , Prolina/metabolismo , Espanha , Água/metabolismo
9.
Chem Res Toxicol ; 35(8): 1312-1333, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35921496

RESUMO

Per- and polyfluoroalkyl substances (PFAS) are a group of persistent environmental pollutants that are ubiquitously found in the environment and virtually in all living organisms, including humans. PFAS cross the blood-brain barrier and accumulate in the brain. Thus, PFAS are a likely risk for neurotoxicity. Studies that measured PFAS levels in the brains of humans, polar bears, and rats have demonstrated that some areas of the brain accumulate greater amounts of PFAS. Moreover, in humans, there is evidence that PFAS exposure is associated with attention-deficit/hyperactivity disorder (ADHD) in children and an increased cause of death from Parkinson's disease and Alzheimer's disease in elderly populations. Given possible links to neurological disease, critical analyses of possible mechanisms of neurotoxic action are necessary to advance the field. This paper critically reviews studies that investigated potential mechanistic causes for neurotoxicity including (1) a change in neurotransmitter levels, (2) dysfunction of synaptic calcium homeostasis, and (3) alteration of synaptic and neuronal protein expression and function. We found growing evidence that PFAS exposure causes neurotoxicity through the disruption of neurotransmission, particularly the dopamine and glutamate systems, which are implicated in age-related psychiatric illnesses and neurodegenerative diseases. Evaluated research has shown there are highly reproduced increased glutamate levels in the hippocampus and catecholamine levels in the hypothalamus and decreased dopamine in the whole brain after PFAS exposure. There are significant gaps in the literature relative to the assessment of the nigrostriatal system (striatum and ventral midbrain) among other regions associated with PFAS-associated neurologic dysfunction observed in humans. In conclusion, evidence suggests that PFAS may be neurotoxic and associated with chronic and age-related psychiatric illnesses and neurodegenerative diseases. Thus, it is imperative that future mechanistic studies assess the impact of PFAS and PFAS mixtures on the mechanism of neurotransmission and the consequential functional effects.


Assuntos
Poluentes Ambientais , Fluorcarbonetos , Síndromes Neurotóxicas , Idoso , Animais , Criança , Dopamina/metabolismo , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Glutamatos , Humanos , Síndromes Neurotóxicas/metabolismo , Ratos , Transmissão Sináptica
10.
Proc Natl Acad Sci U S A ; 119(34): e2206129119, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35969794

RESUMO

The Amino Acid-Polyamine-Organocation (APC) transporter GadC contributes to the survival of pathogenic bacteria under extreme acid stress by exchanging extracellular glutamate for intracellular γ-aminobutyric acid (GABA). Its structure, determined in an inward-facing conformation at alkaline pH, consists of the canonical LeuT-fold with a conserved five-helix inverted repeat, thereby resembling functionally divergent transporters such as the serotonin transporter SERT and the glucose-sodium symporter SGLT1. However, despite this structural similarity, it is unclear if the conformational dynamics of antiporters such as GadC follow the blueprint of these or other LeuT-fold transporters. Here, we used double electron-electron resonance (DEER) spectroscopy to monitor the conformational dynamics of GadC in lipid bilayers in response to acidification and substrate binding. To guide experimental design and facilitate the interpretation of the DEER data, we generated an ensemble of structural models in multiple conformations using a recently introduced modification of AlphaFold2 . Our experimental results reveal acid-induced conformational changes that dislodge the Cterminus from the permeation pathway coupled with rearrangement of helices that enables isomerization between inward- and outward-facing states. The substrate glutamate, but not GABA, modulates the dynamics of an extracellular thin gate without shifting the equilibrium between inward- and outward-facing conformations. In addition to introducing an integrated methodology for probing transporter conformational dynamics, the congruence of the DEER data with patterns of structural rearrangements deduced from ensembles of AlphaFold2 models illuminates the conformational cycle of GadC underpinning transport and exposes yet another example of the divergence between the dynamics of different families in the LeuT-fold.


Assuntos
Antiporters , Proteínas de Bactérias , Proteínas de Membrana , Conformação Proteica , Antiporters/química , Proteínas de Bactérias/química , Espectroscopia de Ressonância de Spin Eletrônica , Glutamatos , Concentração de Íons de Hidrogênio , Proteínas de Membrana/química , Modelos Moleculares , Simulação de Dinâmica Molecular , Ácido gama-Aminobutírico
11.
Cells ; 11(16)2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-36010673

RESUMO

Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene in human glioblastoma (GBM). Hypoxia upregulated GPT2 mRNA and protein levels in GBM cells, which required HIF-2 but not HIF-1. HIF-2 directly bound to the hypoxia response element of the human GPT2 gene, leading to its transcription in hypoxic GBM cells. GPT2 located at the nucleus and mitochondria and reduced α-ketoglutarate levels in GBM cells. Genetic or pharmacological inhibition of GPT2 decreased GBM cell growth and migration under normoxia and hypoxia. Knockout of GPT2 inhibited GBM tumor growth in mice. Collectively, these findings uncover a hypoxia-inducible aminotransferase GPT2 required for GBM progression.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Glioblastoma , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glutamatos , Humanos , Hipóxia , Camundongos , Camundongos Knockout , Transaminases/genética
12.
Phytomedicine ; 105: 154363, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35926378

RESUMO

BACKGROUND: Secondary brain injury (SBI) has been confirmed as a leading cause for the poor prognosis of patients suffering from intracerebral hemorrhage (ICH). SBI co-exists in ischemia and hemorrhagic stroke. Neuro-excitotoxicity is considered the initiating factor of ICH-induced SBI. Our previous research has revealed alpha-asarone (ASA)'s efficacy against cerebral ischemia-reperfusion stroke by mitigating neuro-excitotoxicity. It is not yet known if ASA exhibit neuroprotection against ICH. PURPOSE: This work aimed to investigate ASA's therapeutic effects and potential mechanisms of action against ICH in a classic rat model induced by collagenase Ⅶ injection. METHODS: An in vivo ICH model of Sprague-Dawley rats was established by collagenase Ⅶ injection. We administrated different ASA doses (10, 20, or 40 mg/kg, i.p.) at 2 h post-ICH. Then, rats' short- and long-term neurobehavioral function, bodyweight change, and learning and memory ability were blindly evaluated. Histological, Nissl, and flow cytometry were applied to assess the neuronal damage post-ICH. The wet/dry method and Evans blue extravasation estimated brain edema and blood-brain barrier function. Pathway-related proteins were investigated by immunofluorescence staining, enzyme-linked immunosorbent assay, and Western-blot analysis. RESULTS: The results demonstrated that ASA ameliorated neurological deterioration, bodyweight loss, and learning and memory ability of ICH rats. Histological, Nissl, and flow cytometry analyses showed that ASA reduced neuronal damage and apoptosis post-ICH. Besides, ASA probably mitigated brain edema and blood-brain barrier dysfunction via inhibiting astrocyte activation and consequent pro-inflammatory response. The mechanism investigation attributed ASA's efficacy to the following aspects: 1) promoting sodium ion excretion, thus blocking excitatory signal transduction along the axon; 2) preventing glutamate-involved pathways, i.e., decrease of N-methyl-d-aspartic acid receptor subunit 2B, increase of glutamate transporter-1, and alleviation of calcium-related cascades, mitochondrion-associated apoptosis, and neuronal autophagy; 3) enhancing the expression of GABAARs, thus abating neuronal excitotoxicity. CONCLUSION: Our study first confirmed the effect of ASA on ameliorating the neurobehavioral deterioration of ICH rats, possibly via alleviation of glutamate-involved neuro-excitotoxicity, i.e., calcium cascades, mitochondrion-involved apoptosis, neuronal autophagy, and astrocyte-related inflammation. These findings not only provided a promising drug candidate for clinical treatment of ICH but also shed light on the future drug discovery against ICH.


Assuntos
Edema Encefálico , Lesões Encefálicas , Derivados de Alilbenzenos , Animais , Anisóis , Apoptose , Cálcio , Hemorragia Cerebral , Modelos Animais de Doenças , Glutamatos , Ratos , Ratos Sprague-Dawley
13.
Nutrients ; 14(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36014812

RESUMO

Three metabolite patterns have previously shown prospective inverse associations with the risk of aggressive prostate cancer within the European Prospective Investigation into Cancer and Nutrition (EPIC). Here, we investigated dietary and lifestyle correlates of these three prostate cancer-related metabolite patterns, which included: 64 phosphatidylcholines and three hydroxysphingomyelins (Pattern 1), acylcarnitines C18:1 and C18:2, glutamate, ornithine, and taurine (Pattern 2), and 8 lysophosphatidylcholines (Pattern 3). In a two-stage cross-sectional discovery (n = 2524) and validation (n = 518) design containing 3042 men free of cancer in EPIC, we estimated the associations of 24 dietary and lifestyle variables with each pattern and the contributing individual metabolites. Associations statistically significant after both correction for multiple testing (False Discovery Rate = 0.05) in the discovery set and at p < 0.05 in the validation set were considered robust. Intakes of alcohol, total fish products, and its subsets total fish and lean fish were positively associated with Pattern 1. Body mass index (BMI) was positively associated with Pattern 2, which appeared to be driven by a strong positive BMI-glutamate association. Finally, both BMI and fatty fish were inversely associated with Pattern 3. In conclusion, these results indicate associations of fish and its subtypes, alcohol, and BMI with metabolite patterns that are inversely associated with risk of aggressive prostate cancer.


Assuntos
Dieta , Neoplasias da Próstata , Animais , Índice de Massa Corporal , Estudos Transversais , Dieta/efeitos adversos , Peixes , Glutamatos , Humanos , Masculino , Estudos Prospectivos , Neoplasias da Próstata/etiologia , Fatores de Risco
14.
Curr Biol ; 32(16): 3564-3575.e5, 2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-35961314

RESUMO

Behavioral activities that require control over automatic routines typically feel effortful and result in cognitive fatigue. Beyond subjective report, cognitive fatigue has been conceived as an inflated cost of cognitive control, objectified by more impulsive decisions. However, the origins of such control cost inflation with cognitive work are heavily debated. Here, we suggest a neuro-metabolic account: the cost would relate to the necessity of recycling potentially toxic substances accumulated during cognitive control exertion. We validated this account using magnetic resonance spectroscopy (MRS) to monitor brain metabolites throughout an approximate workday, during which two groups of participants performed either high-demand or low-demand cognitive control tasks, interleaved with economic decisions. Choice-related fatigue markers were only present in the high-demand group, with a reduction of pupil dilation during decision-making and a preference shift toward short-delay and little-effort options (a low-cost bias captured using computational modeling). At the end of the day, high-demand cognitive work resulted in higher glutamate concentration and glutamate/glutamine diffusion in a cognitive control brain region (lateral prefrontal cortex [lPFC]), relative to low-demand cognitive work and to a reference brain region (primary visual cortex [V1]). Taken together with previous fMRI data, these results support a neuro-metabolic model in which glutamate accumulation triggers a regulation mechanism that makes lPFC activation more costly, explaining why cognitive control is harder to mobilize after a strenuous workday.


Assuntos
Cognição , Córtex Pré-Frontal , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Cognição/fisiologia , Tomada de Decisões/fisiologia , Glutamatos , Humanos , Córtex Pré-Frontal/fisiologia , Recompensa
15.
Front Immunol ; 13: 951137, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990657

RESUMO

Background: Currently available prognostic tools and focused therapeutic methods result in unsatisfactory treatment of gastric cancer (GC). A deeper understanding of human epidermal growth factor receptor 2 (HER2)-coexpressed metabolic pathways may offer novel insights into tumour-intrinsic precision medicine. Methods: The integrated multi-omics strategies (including transcriptomics, proteomics and metabolomics) were applied to develop a novel metabolic classifier for gastric cancer. We integrated TCGA-STAD cohort (375 GC samples and 56753 genes) and TCPA-STAD cohort (392 GC samples and 218 proteins), and rated them as transcriptomics and proteomics data, resepectively. 224 matched blood samples of GC patients and healthy individuals were collected to carry out untargeted metabolomics analysis. Results: In this study, pan-cancer analysis highlighted the crucial role of ERBB2 in the immune microenvironment and metabolic remodelling. In addition, the metabolic landscape of GC indicated that alanine, aspartate and glutamate (AAG) metabolism was significantly associated with the prevalence and progression of GC. Weighted metabolite correlation network analysis revealed that glycolysis/gluconeogenesis (GG) and AAG metabolism served as HER2-coexpressed metabolic pathways. Consensus clustering was used to stratify patients with GC into four subtypes with different metabolic characteristics (i.e. quiescent, GG, AAG and mixed subtypes). The GG subtype was characterised by a lower level of ERBB2 expression, a higher proportion of the inflammatory phenotype and the worst prognosis. However, contradictory features were found in the mixed subtype with the best prognosis. The GG and mixed subtypes were found to be highly sensitive to chemotherapy, whereas the quiescent and AAG subtypes were more likely to benefit from immunotherapy. Conclusions: Transcriptomic and proteomic analyses highlighted the close association of HER-2 level with the immune status and metabolic features of patients with GC. Metabolomics analysis highlighted the co-expressed relationship between alanine, aspartate and glutamate and glycolysis/gluconeogenesis metabolisms and HER2 level in GC. The novel integrated multi-omics strategy used in this study may facilitate the development of a more tailored approach to GC therapy.


Assuntos
Neoplasias Gástricas , Alanina , Ácido Aspártico/genética , Glutamatos/genética , Humanos , Imunoterapia , Metabolômica , Terapia Neoadjuvante , Proteômica , Receptor ErbB-2 , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Transcriptoma , Microambiente Tumoral/genética
16.
Behav Brain Res ; 435: 114035, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-35926562

RESUMO

Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and ß-amyloid (Aß). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10 µg/10 µL) and Aß (5 µg/2.5 µL) into the left ventricle and prefrontal cortex, respectively. AMI (10 mg/kg/day, i.p.), RIVA (2 mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.


Assuntos
Doença por Corpos de Lewy , Amitriptilina , Animais , Cognição , Glutamatos , Doença por Corpos de Lewy/tratamento farmacológico , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Masculino , Ratos , Ratos Wistar , alfa-Sinucleína/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-35944825

RESUMO

Butachlor herbicide belongs to the family of chloroacetanilide group, widely used for control of grass and broadleaf weeds in paddy fields however, its repeated application may result in aquatic pollution. Butachlor residue has been detected in aquatic environments, which may produce toxic effects on non-target organisms including fish. Keeping this in mind, the present study was designed to estimate the LC50 of butachlor (Shaktiman®), and to evaluate the sub-lethal toxicity at two concentrations (12.42 µg L-1 and 62.10 µg L-1) in Labeo rohita for a period of 24, 48, and 72 h. Fish exposed to butachlor reduced the counts of red blood cells (RBC), haemoglobin (HGB), hematocrit (HCT), and white blood cells (WBC). A significant (p < 0.05) increase in the antioxidant enzyme (superoxide dismutase-SOD, glutathione-s-transferase-GST), and hepatic enzyme (glutamate-oxaloacetate transaminase-GOT, glutamate-pyruvate transaminase-GPT) were noticed in butachlor exposed fish. Heat shock protein 70 (HSP70) and HSP90 in gill; cortisol, protein, albumin, globulin, and triglyceride in serum were increased upon exposure of butachlor. On the contrary, complement 3 (C3) and immunoglobulin (IgM) in serum was found to be decreased compared to control fish. The findings thus suggest that the fish upon exposure to butachlor disrupts the biomarkers which ultimately leads to growth retardation in fish.


Assuntos
Cyprinidae , Poluentes Químicos da Água , Acetanilidas , Animais , Aspartato Aminotransferases/metabolismo , Biomarcadores/metabolismo , Cyprinidae/metabolismo , Glutamatos/metabolismo , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade
18.
J Org Chem ; 87(17): 11816-11825, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35952660

RESUMO

The side-chain functionalization of aspartic/glutamic acid derivatives through photoinduced decarboxylation was achieved by using organic two-molecule photoredox catalysts without racemization under mild conditions. A facile process involving the preparation of substrates and photoinduced decarboxylative radical additions can provide easy access to the linked amino acids with carbohydrates and amino acids at the side chain.


Assuntos
Glutamatos , Processos Fotoquímicos , Aminoácidos/química , Estrutura Molecular , Oxirredução
19.
J Vis Exp ; (186)2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-36036615

RESUMO

Cell-free protein synthesis (CFPS) has recently become very popular in the field of synthetic biology due to its numerous advantages. Using linear DNA templates for CFPS will further enable the technology to reach its full potential, decreasing the experimental time by eliminating the steps of cloning, transformation, and plasmid extraction. Linear DNA can be rapidly and easily amplified by PCR to obtain high concentrations of the template, avoiding potential in vivo expression toxicity. However, linear DNA templates are rapidly degraded by exonucleases that are naturally present in the cell extracts. There are several strategies that have been proposed to tackle this problem, such as adding nuclease inhibitors or chemical modification of linear DNA ends for protection. All these strategies cost extra time and resources and are yet to obtain near-plasmid levels of protein expression. A detailed protocol for an alternative strategy is presented here for using linear DNA templates for CFPS. By using cell extracts from exonuclease-deficient knockout cells, linear DNA templates remain intact without requiring any end-modifications. We present the preparation steps of cell lysate from Escherichia coli BL21 Rosetta2 ΔrecBCD strain by sonication lysis and buffer calibration for Mg-glutamate (Mg-glu) and K-glutamate (K-glu) specifically for linear DNA. This method is able to achieve protein expression levels comparable to that from plasmid DNA in E. coli CFPS.


Assuntos
Escherichia coli , Exonucleases , Extratos Celulares , Sistema Livre de Células , DNA/genética , DNA/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Exonucleases/metabolismo , Glutamatos , Moldes Genéticos
20.
Medicine (Baltimore) ; 101(34): e30092, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36042671

RESUMO

Graves disease (GD) and type 2 diabetes mellitus (T2DM) both impair liver function; we therefore explored the possibility of a relationship among diabetic control, thyroid function, and liver function. This retrospective, cross-sectional study compared serum liver function biomarkers of primary GD patients in a single center between 2016 and 2020, derived from clinical databases, and clarified the correlation of liver function in GD patients with or without T2DM. Furthermore, the diabetes mellitus group was divided into glycated hemoglobin A1C (HbA1C) <6.5% group and ≥6.5% group to further analyze the effect by disease control in patients. Statistical differences between groups were assessed using independent t tests to clarify the association of serum biomarkers between GD with T2DM. Pearson test was applied to assess within-group statistical correlation of serum biomarkers. The correlation of factors in each group was demonstrated by using the Kendall tau-b method and stepwise regression analysis. A total of 77 patients were included in the study. In the study population, glutamate pyruvate transaminase (GPT) was significantly correlated with thyroid-stimulating hormone, and HbA1C was significantly correlated with alkaline phosphatase (ALK-P), glutamate oxaloacetate transaminase (GOT), and GPT. An examination of GOT, GPT, free thyroxine (FT4), and HbA1C levels revealed a significant difference between the non-T2DM and T2DM groups. GPT also exhibited a significant correlation with triiodothyronine in the T2DM group. The T2DM group was further divided into groups: HbA1C <6.5% and ≥6.5%. The results demonstrated that ALK-P, GOT, GPT, and FT4 levels were significantly different between the groups. A significant correlation between ALK-P and thyroid-stimulating hormone and between GOT and FT4 was also identified in the HbA1C <6.5% group. Our single-center study revealed that diabetes affects liver function in patients with GD. For patients with T2DM, when liver function becomes impaired, thyroid function control deteriorates. GPT was correlated with triiodothyronine but not with FT4, which indicated the impairment of deiodination in the liver. This phenomenon was not observed in the non-T2DM population. The early detection of abnormal liver function in patients with GD and T2DM may help limit the development of comorbidities and improve disease management.


Assuntos
Diabetes Mellitus Tipo 2 , Doença de Graves , Alanina Transaminase , Aspartato Aminotransferases , Biomarcadores , Estudos Transversais , Glutamatos , Hemoglobina A Glicada , Doença de Graves/complicações , Humanos , Receptores Proteína Tirosina Quinases , Estudos Retrospectivos , Taiwan/epidemiologia , Tireotropina , Tiroxina , Tri-Iodotironina
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