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2.
Front Public Health ; 10: 969113, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36062104

RESUMO

Background: In previous questionnaire surveys of miners, sleep disorders were found among underground workers. The influence of the special deep-underground environment and its potential mechanism are still unclear. Therefore, this study intends to utilize LC-MS metabolomics to study the potential differences between different environments and different sleep qualities. Methods: Twenty-seven miners working at 645-1,500 m deep wells were investigated in this study, and 12 local ground volunteers were recruited as the control group. The Pittsburgh Sleep Quality Index (PSQI) was used to examine and evaluate the sleep status of the subjects in the past month, and valuable basic information about the participants was collected. PSQI scores were obtained according to specific calculation rules, and the corresponding sleep grouping and subsequent analysis were carried out. Through liquid chromatography-mass spectrometry (LC-MS) non-targeted metabolomics analysis, differences in metabolism were found by bioinformatics analysis in different environments. Results: Between the deep-underground and ground (DUvsG) group, 316 differential metabolites were identified and 125 differential metabolites were identified in the good sleep quality vs. poor sleep quality (GSQvsPSQ) group. The metabolic pathways of Phenylalanine, tyrosine and tryptophan biosynthesis (p = 0.0102) and D-Glutamine and D-glutamate metabolism (p = 0.0241) were significantly enriched in DUvsG. For GSQvsPSQ group, Butanoate metabolism was statistically significant (p = 0.0276). L-Phenylalanine, L-Tyrosine and L-Glutamine were highly expressed in the deep-underground group. Acetoacetic acid was poorly expressed, and 2-hydroxyglutaric acid was highly expressed in good sleep quality. Conclusions: The influence of the underground environment on the human body is more likely to induce specific amino acid metabolism processes, and regulate the sleep-wake state by promoting the production of excitatory neurotransmitters. The difference in sleep quality may be related to the enhancement of glycolytic metabolism, the increase in excitatory neurotransmitters and the activation of proinflammation. L-phenylalanine, L-tyrosine and L-glutamine, Acetoacetic acid and 2-hydroxyglutaric acid may be potential biomarkers correspondingly.


Assuntos
Glutamina , Qualidade do Sono , Humanos , Neurotransmissores , Fenilalanina , Projetos Piloto , Tirosina
3.
J Pharmacol Sci ; 150(2): 74-80, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055754

RESUMO

PURPOSE: Peficitinib and tofacitinib are known to suppress inflammation in rheumatoid arthritis (RA) by inhibiting Janus kinases (JAKs). However, these effects on tyrosine kinases other than JAKs have not yet been well investigated. We evaluated the effects of peficitinib and tofacitinib on platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) and on the activation of fibroblast-like synoviocytes (FLSs) and endothelial cells, main pathological causes of RA. METHODS: Peficitinib and tofacitinib were tested in PDGF and VEGF RTK assays. We then used FLSs derived from RA patient (RA-FLSs) and human umbilical vein endothelial cells (HUVECs) to study the effects of peficitinib and tofacitinib on PDGF- and VEGF-induced signal transduction and on the activation of RA-FLSs and endothelial cell tube formation. FINDINGS: Peficitinib, not tofacitinib, inhibited both PDGF and VEGF RTKs in addition to JAKs in cell-free assay system. Peficitinib and tofacitinib attenuated PDGF- and VEGF-induced intracellular signal transduction pathways in RA-FLSs and HUVECs to varying degrees. Only peficitinib potently inhibited PDGF-induced secretion of interleukin-6, VEGF, and matrix metalloproteinase-3 in RA-FLSs, and endothelial cell tube formation by HUVECs. CONCLUSION: Peficitinib may improve RA through inhibition of PDGF and VEGF signal transduction, in addition to JAK inhibition.


Assuntos
Artrite Reumatoide , Sinoviócitos , Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Células Cultivadas , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Janus Quinases , Niacinamida/análogos & derivados , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Transdução de Sinais , Sinoviócitos/patologia , Tirosina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/farmacologia
4.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077173

RESUMO

A new synthesis method is described for the first time to produce silver nanoclusters (AgNCs) by using the tyrosine (Tyr) amino acid. Several important parameters (e.g., molar ratios, initial pH, reaction time etc.) were optimized to reach the highest yield. The formed Tyr-AgNCs show characteristic blue emission at λem = 410 nm, and two dominant fluorescence lifetime components were deconvoluted (τ1 ~ 3.7 and τ2 ~ 4.9 ns). The NCs contained metallic cores stabilized by dityrosine. For possible application, the interactions with several metal ions from the tap water and wastewater were investigated. Among the studied cations, four different ions (Cu2+, Ni2+, Fe3+, and Rh3+) had a dominant effect on the fluorescence of NCs. Based on the detected quenching processes, the limit of detection of the metal ions was determined. Static quenching (formation of a non-luminescent complex) was observed in all cases by temperature-dependent measurements. The calculated thermodynamic parameters showed that the interactions are spontaneous ranked in the following order of strength: Cu2+ > Fe3+ > Rh3+ > Ni2+. Based on the sign and relations of the standard enthalpy (ΔH°) and entropy changes (ΔS°), the dominant forces were also identified.


Assuntos
Nanopartículas Metálicas , Cátions , Cobre/química , Fluorescência , Íons , Nanopartículas Metálicas/química , Prata/química , Espectrometria de Fluorescência/métodos , Tirosina
5.
Nat Commun ; 13(1): 5434, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114189

RESUMO

Despite the great promise of genetic code expansion technology to modulate structures and functions of proteins, external addition of ncAAs is required in most cases and it often limits the utility of genetic code expansion technology, especially to noncanonical amino acids (ncAAs) with poor membrane internalization. Here, we report the creation of autonomous cells, both prokaryotic and eukaryotic, with the ability to biosynthesize and genetically encode sulfotyrosine (sTyr), an important protein post-translational modification with low membrane permeability. These engineered cells can produce site-specifically sulfated proteins at a higher yield than cells fed exogenously with the highest level of sTyr reported in the literature. We use these autonomous cells to prepare highly potent thrombin inhibitors with site-specific sulfation. By enhancing ncAA incorporation efficiency, this added ability of cells to biosynthesize ncAAs and genetically incorporate them into proteins greatly extends the utility of genetic code expansion methods.


Assuntos
Código Genético , Trombina , Aminoácidos/química , Proteínas/metabolismo , Trombina/genética , Tirosina/metabolismo
6.
Commun Biol ; 5(1): 982, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114357

RESUMO

Topoisomerase I (TOP1) controls the topological state of DNA during DNA replication, and its dysfunction due to treatment with an inhibitor, such as camptothecin (CPT), causes replication arrest and cell death. Although CPT has excellent cytotoxicity, it has the disadvantage of instability under physiological conditions. Therefore, new types of TOP1 inhibitor have attracted particular attention. Here, we characterised the effect of a non-camptothecin inhibitor, Genz-644282 (Genz). First, we found that treatment with Genz showed cytotoxicity by introducing double-strand breaks (DSBs), which was suppressed by co-treatment with aphidicolin. Genz-induced DSB formation required the functions of TOP1. Next, we explored the advantages of Genz over CPT and found it was effective against CPT-resistant TOP1 carrying either N722S or N722A mutation. The effect of Genz was also confirmed at the cellular level using a CPT-resistant cell line carrying N722S mutation in the TOP1 gene. Moreover, we found arginine residue 364 plays a crucial role for the binding of Genz. Because tyrosine residue 723 is the active centre for DNA cleavage and re-ligation by TOP1, asparagine residue 722 plays crucial roles in the accessibility of the drug. Here, we discuss the mechanism of action of Genz on TOP1 inhibition.


Assuntos
Camptotecina , DNA Topoisomerases Tipo I , Afidicolina , Arginina , Asparagina , Camptotecina/farmacologia , DNA , DNA Topoisomerases Tipo I/genética , DNA Topoisomerases Tipo I/metabolismo , Naftiridinas , Tirosina
7.
Environ Sci Technol ; 56(18): 13439-13448, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36069735

RESUMO

The rapid proliferation of planktonic algae induced by eutrophication and climate warming make algae dissolved organic matter (AOM) an important source of dissolved organic matter (DOM) in surface waters, but the understanding of the link between AOM composition and photo-reactivity/photo-transformation of DOM in aquatic systems is limited. Here, intracellular organic matter (IOM) from Microcystis aeruginosa was extracted and subjected to molecular weight (MW) fractionation. Results indicated that IOM had lower aromaticity and higher photosensitive activity compared to Suwannee River fulvic acid (SRFA). The photosensitive activity of IOM relied on both its molecular weight distribution and fluorescence components. The IOM fraction with the highest MW proteins had the lowest quantum yields of reactive intermediates (ΦRIs), which increased with the decrease of MW, while the fractions with more low-excitation tyrosine-like components had relatively higher ΦRIs. Parallel factor analysis and high-resolution mass spectrometry revealed that light radiation of IOM resulted in the composition transformation from tryptophan-like and tyrosine-like components to humic-like components, forming less aromatic and more saturated recalcitrant dissolved organic carbon. Our findings provide new insights into the photo-reactivity and photo-transformation of algae-derived organic matters and help to predict DOM formation involved in carbon cycling in water environment.


Assuntos
Matéria Orgânica Dissolvida , Triptofano , Carbono , Substâncias Húmicas/análise , Espectrometria de Massas , Plantas , Espectrometria de Fluorescência/métodos , Tirosina , Água
8.
Front Endocrinol (Lausanne) ; 13: 958442, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133304

RESUMO

Introduction: We present a case of a patient with disseminated ACTH-secreting neuroendocrine neoplasm with biologic heterogeneity between a primary tumor and metastases. The diagnosis was obtained and multidisciplinary management was conducted with a positron emission tomography/computed tomography (PET/CT) scan with Gallium-68 [68Ga]-labeled dodecanetetraacetic acid-tyrosine-3-octreotate ([68Ga]-DOTA-TATE) and Fluor-18 [18F]-fluorodeoxyglucose ([18F]-FDG). Case report: A PET/CT scan revealed a difference between [68Ga]-DOTA-TATE and [18F]-FDG uptake in primary tumor and several metastases. PET/CT showed high [18F]-FDG uptake and lack of [68Ga]-DOTA-TATE in the primary tumor, whereas both [68Ga]-DOTA-TATE and [18F]-FDG hyperaccumulation were identified in the majority of metastases. Despite positive [68Ga]-DOTA-TATE PET/CT, which is associated with high affinity with the somatostatin receptor 2 subtype, immunohistochemical examination revealed overexpression of the somatostatin receptor 5 subtype only. Perhaps, this explained the ineffectiveness of the treatment with "cold" somatostatin analogs. Conclusion: This case had an aggressive clinical course, despite cytoreductive surgical treatment and somatostatin analog therapy. PET/CT imaging with two tracers is a molecular tool that demonstrates a biologic heterogeneity between a primary tumor and metastases and yields additional information that may influence the choice of the patient management strategy.


Assuntos
Produtos Biológicos , Tumores Neuroendócrinos , Hormônio Adrenocorticotrópico , Fluordesoxiglucose F18 , Humanos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Somatostatina , Tirosina
9.
Medicina (Kaunas) ; 58(9)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36143915

RESUMO

Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients' daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient's daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.


Assuntos
Anti-Helmínticos , Antimaláricos , Antineoplásicos , Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Metformina , Monofosfato de Adenosina/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Helmínticos/uso terapêutico , Antibacterianos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antimaláricos/uso terapêutico , Antineoplásicos/uso terapêutico , Atorvastatina/uso terapêutico , Neoplasias da Mama/patologia , Colesterol , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Masculino , Mebendazol/uso terapêutico , Metformina/uso terapêutico , Ácido Mevalônico/uso terapêutico , Propranolol/uso terapêutico , Proteínas Quinases/metabolismo , Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf , Receptores Adrenérgicos beta 2/uso terapêutico , Tirosina
10.
Nutrients ; 14(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36145191

RESUMO

This study investigated the effect of (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone) on palmitate-induced insulin resistance and elucidated the underlying mechanism in L6 skeletal muscle cells. Glucose uptake was markedly decreased due to palmitate-induced insulin resistance in these cells; however, 10, 25, and 50 µM HM-chromanone remarkably improved glucose uptake in a concentration-dependent manner. HM-chromanone treatment downregulated protein tyrosine phosphatase 1B (PTP1B) and phosphorylation of c-Jun N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß), which increased because of palmitate mediating the insulin-resistance status in cells. HM-chromanone promoted insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and suppressed palmitate-induced phosphorylation of IRS-1 serine. This activated phosphoinositide 3-kinase (PI3K) and stimulated protein kinase B (AKT) phosphorylation. Phosphorylated AKT promoted the translocation of Glucose transporter type 4 to the plasma membrane and significantly enhanced glucose uptake into muscle cells. Additionally, HM-chromanone increased glycogen synthesis through phosphorylating glycogen synthase kinase 3 alpha/beta (GSK3 α/ß) via AKT. Consequently, HM-chromanone may improve insulin resistance by downregulating the phosphorylation of IRS-1 serine through inhibition of negative regulators of insulin signaling and inflammation-activated protein kinases in L6 skeletal muscle cells.


Assuntos
Resistência à Insulina , Portulaca , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/fisiologia , Isoflavonas , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fibras Musculares Esqueléticas , Músculo Esquelético/metabolismo , Palmitatos/metabolismo , Palmitatos/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Portulaca/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina/metabolismo , Tirosina/metabolismo
11.
Front Immunol ; 13: 866564, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36159830

RESUMO

One of the most common symptoms in COVID-19 is a sudden loss of smell. SARS-CoV-2 has been detected in the olfactory bulb (OB) from animal models and sporadically in COVID-19 patients. To decipher the specific role over the SARS-CoV-2 proteome at olfactory level, we characterized the in-depth molecular imbalance induced by the expression of GFP-tagged SARS-CoV-2 structural proteins (M, N, E, S) on mouse OB cells. Transcriptomic and proteomic trajectories uncovered a widespread metabolic remodeling commonly converging in extracellular matrix organization, lipid metabolism and signaling by receptor tyrosine kinases. The molecular singularities and specific interactome expression modules were also characterized for each viral structural factor. The intracellular molecular imbalance induced by each SARS-CoV-2 structural protein was accompanied by differential activation dynamics in survival and immunological routes in parallel with a differentiated secretion profile of chemokines in OB cells. Machine learning through a proteotranscriptomic data integration uncovered TGF-beta signaling as a confluent activation node by the SARS-CoV-2 structural proteome. Taken together, these data provide important avenues for understanding the multifunctional immunomodulatory properties of SARS-CoV-2 M, N, S and E proteins beyond their intrinsic role in virion formation, deciphering mechanistic clues to the olfactory inflammation observed in COVID-19 patients.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Camundongos , Proteoma , Proteômica , Fator de Crescimento Transformador beta , Tirosina
12.
Proc Natl Acad Sci U S A ; 119(40): e2207374119, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161920

RESUMO

Most colonial marine invertebrates are capable of allorecognition, the ability to distinguish between themselves and conspecifics. One long-standing question is whether invertebrate allorecognition genes are homologous to vertebrate histocompatibility genes. In the cnidarian Hydractinia symbiolongicarpus, allorecognition is controlled by at least two genes, Allorecognition 1 (Alr1) and Allorecognition 2 (Alr2), which encode highly polymorphic cell-surface proteins that serve as markers of self. Here, we show that Alr1 and Alr2 are part of a family of 41 Alr genes, all of which reside in a single genomic interval called the Allorecognition Complex (ARC). Using sensitive homology searches and highly accurate structural predictions, we demonstrate that the Alr proteins are members of the immunoglobulin superfamily (IgSF) with V-set and I-set Ig domains unlike any previously identified in animals. Specifically, their primary amino acid sequences lack many of the motifs considered diagnostic for V-set and I-set domains, yet they adopt secondary and tertiary structures nearly identical to canonical Ig domains. Thus, the V-set domain, which played a central role in the evolution of vertebrate adaptive immunity, was present in the last common ancestor of cnidarians and bilaterians. Unexpectedly, several Alr proteins also have immunoreceptor tyrosine-based activation motifs and immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails, suggesting they could participate in pathways homologous to those that regulate immunity in humans and flies. This work expands our definition of the IgSF with the addition of a family of unusual members, several of which play a role in invertebrate histocompatibility.


Assuntos
Hidrozoários , Invertebrados , Animais , Humanos , Imunoglobulinas/química , Imunoglobulinas/genética , Invertebrados/genética , Complexo Principal de Histocompatibilidade/genética , Proteínas de Membrana/genética , Tirosina/genética
13.
Nucleic Acids Res ; 50(17): 10026-10040, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36107766

RESUMO

Abortive infection (Abi) is a bacterial antiphage defense strategy involving suicide of the infected cell. Some Abi pathways involve polymerases that are related to reverse transcriptases. They are unique in the way they combine the ability to synthesize DNA in a template-independent manner with protein priming. Here, we report crystal and cryo-electron microscopy structures of two Abi polymerases: AbiK and Abi-P2. Both proteins adopt a bilobal structure with an RT-like domain that comprises palm and fingers subdomains and a unique helical domain. AbiK and Abi-P2 adopt a hexameric and trimeric configuration, respectively, which is unprecedented for reverse transcriptases. Biochemical experiments showed that the formation of these oligomers is required for the DNA polymerization activity. The structure of the AbiK-DNA covalent adduct visualized interactions between the 3' end of DNA and the active site and covalent attachment of the 5' end of DNA to a tyrosine residue used for protein priming. Our data reveal a structural basis of the mechanism of highly unusual template-independent protein-priming polymerases.


Assuntos
DNA , DNA Polimerase Dirigida por RNA , Sequência de Aminoácidos , Microscopia Crioeletrônica , RNA Polimerases Dirigidas por DNA/metabolismo , Humanos , DNA Polimerase Dirigida por RNA/metabolismo , Tirosina
14.
Int J Mol Sci ; 23(18)2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36142560

RESUMO

The aim of the study was to investigate the effects of short-term oral administration of inorganic nitrate (NaNO3; n = 8) or placebo (NaCl; n = 9) (each 0.1 mmol/kg body weight/d for 9 days) on plasma amino acids, creatinine, and oxidative stress in healthy young men. At baseline, the plasma concentrations of amino acids did not differ between the groups. At the end of the study, the plasma concentrations of homoarginine (hArg; by 24%, p = 0.0001), citrulline and ornithine (Cit/Orn; by 16%, p = 0.015), and glutamine/glutamate (Gln/Glu; by 6%, p = 0.0003) were higher in the NaNO3 group compared to the NaCl group. The plasma concentrations of sarcosine (Sarc; by 28%, p < 0.0001), tyrosine (by 14%, p = 0.0051), phenylalanine (by 8%, p = 0.0026), and tryptophan (by 8%, p = 0.0047) were lower in the NaNO3 group compared to the NaCl group. These results suggest that nitrate administration affects amino-acid metabolism. The arginine/glycine amidinotransferase (AGAT) catalyzes two reactions: (1) the formation of l-homoarginine (hArg) and l-ornithine (Orn) from l-arginine (Arg) and l-lysine (Lys): Arg + Lys <-> hArg + Orn, with equilibrium constant Kharg; (2) the formation of guanidinoacetate (GAA) and Orn from Arg and glycine (Gly): Arg + Gly <-> GAA + Orn, with equilibrium constant Kgaa. The plasma Kgaa/KhArg ratio was lower in the NaNO3 group compared to the NaCl group (1.57 vs. 2.02, p = 0.0034). Our study suggests that supplementation of inorganic nitrate increases the AGAT-catalyzed synthesis of hArg and decreases the N-methyltransferase-catalyzed synthesis of GAA, the precursor of creatine. To our knowledge, this is the first study to demonstrate elevation of hArg synthesis by inorganic nitrate supplementation. Remarkably, an increase of 24% corresponds to the synthesis capacity of one kidney in healthy humans. Differences in the association between plasma concentrations of amino acids in the NaNO3 and NaCl groups suggest changes in amino-acid homeostasis. Plasma concentrations of the oxidative stress marker malondialdehyde (MDA) did not change after supplementation of NaNO3 or NaCl over the whole exercise time range. Plasma nitrite concentration turned out to be a more discriminant marker of NaNO3 ingestion than plasma nitrate (area under the receiver operating characteristic curve: 0.951 vs. 0.866, p < 0.0001 each).


Assuntos
Homoarginina , Nitratos , Arginina/metabolismo , Citrulina , Creatina , Creatinina , Suplementos Nutricionais , Glutamatos , Glutamina , Glicina , Homoarginina/metabolismo , Humanos , Lisina , Masculino , Malondialdeído , Metiltransferases , Nitritos , Ornitina , Fenilalanina , Sarcosina , Cloreto de Sódio , Triptofano , Tirosina
15.
Sci Rep ; 12(1): 16083, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167967

RESUMO

Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701-900 (105), 901-1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR (p < 0.001), while HPLA/TYR ratio decreased (p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.


Assuntos
Alcaptonúria , Encefalopatias Metabólicas Congênitas , Tirosinemias , Alcaptonúria/tratamento farmacológico , Cicloexanonas/uso terapêutico , Ácido Homogentísico , Humanos , Nitrobenzoatos/uso terapêutico , Fenilalanina , Fenilpropionatos , Tirosina/metabolismo , Tirosinemias/tratamento farmacológico
16.
J Exp Med ; 219(12)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36169652

RESUMO

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Serina , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Treonina , Fator de Necrose Tumoral alfa/metabolismo , Tirosina
17.
Sci Rep ; 12(1): 15847, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36151233

RESUMO

Alzheimer's disease (AD) involves pathological processing of amyloid precursor protein (APP) into amyloid-ß and microtubule associated protein Tau (MAPT) into hyperphosphorylated Tau tangles leading to neurodegeneration. Only 5% of AD cases are familial making it difficult to predict who will develop the disease thereby hindering our ability to treat the causes of the disease. A large population who almost certainly will, are those with Down syndrome (DS), who have a 90% lifetime incidence of AD. DS is caused by trisomy of chromosome 21 resulting in three copies of APP and other AD-associated genes, like dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) overexpression. This implies that DYRK1a inhibitors may have therapeutic potential for DS and AD, however It is not clear how overexpression of each of these genes contributes to the pathology of each disease as well as how effective a DYRK1A inhibitor would be at suppressing any of these. To address this knowledge gap, we used Drosophila models with human Tau, human amyloid-ß or fly DYRK1A (minibrain (mnb)) neuronal overexpression resulting in photoreceptor neuron degeneration, premature death, decreased locomotion, sleep and memory loss. DYRK1A small molecule Type 1 kinase inhibitors (DYR219 and DYR533) were effective at suppressing these disease relevant phenotypes confirming their therapeutic potential.


Assuntos
Doença de Alzheimer , Síndrome de Down , Síndromes Neurotóxicas , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Fosforilação , Tirosina/metabolismo , Proteínas tau/metabolismo
18.
Phytomedicine ; 106: 154417, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36063584

RESUMO

BACKGROUND: Securinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four rings, including three chiral centers. It has been suggested that securinine can be chemically synthesized from tyrosine and lysine. Securinine has long been used to treat central nervous system diseases. In recent years, more and more evidence shows that securinine also has anticancer activity, which has not been systematically discussed and analyzed. PURPOSE: This study aims to propose an overall framework to describe the molecular targets of securinine in different signal pathways, and discuss the current status and prospects of each pathway, so as to provide a theoretical basis for the development securinine as an effective anticancer drug. METHODS: The research databases on the anticancer activity of securinine from PubMed, Scopus, Web of Science and ScienceDirect to 2021 were systematically searched. This paper follows the Preferred Reporting Items and Meta-Analysis guidelines. RESULTS: Securinine has the ability to kill a variety of human cancer cells, including, leukemia as well as prostate, cervical, breast, lung, and colon cancer cells. It can regulate the signal pathways of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, Wnt and Janus kinase-signal transducer and activator of transcription, promote cancer cell apoptosis and autophagy, and inhibit cancer cell metastasis. Securinine also has the activity of inducing leukemia cell differentiation. CONCLUSION: Although there has been some experimental evidence indicating the anticancer effect of securinine and its possible pharmacology, in order to design more effective anticancer drugs, it is necessary to study the synergy of intracellular signaling pathways. More in vivo experiments and even clinical studies are needed, and the synergy between securinine and other drugs is also worth studying.


Assuntos
Alcaloides , Leucemia , Azepinas , Linhagem Celular Tumoral , Compostos Heterocíclicos de Anel em Ponte , Humanos , Janus Quinases , Lactonas/farmacologia , Leucemia/tratamento farmacológico , Lisina , Masculino , Fosfatidilinositóis , Piperidinas , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Tirosina
19.
Sci Rep ; 12(1): 15095, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064958

RESUMO

Phosphorylation controls important cellular signals and its dysregulation leads to disease. While most phospho-regulation studies are focused on kinases, phosphatases are comparatively overlooked. Combining peptide arrays with SAMDI mass spectrometry, we show that tyrosine phosphatase activity is restricted by basic amino acids adjacent to phosphotyrosines. We validate this model using two ß-catenin mutants associated with cancer (T653R/K) and a mouse model for intellectual disability (T653K). These mutants introduce a basic residue next to Y654, an established phosphorylation site where modification shifts ß-catenin from cell-cell adhesions and towards its essential nuclear role as Wnt-signaling effector. We show that T653-basic mutant ß-catenins are less efficiently dephosphorylated by phosphatases, leading to sustained Y654 phosphorylation and elevated Wnt signals, similar to those observed for Y654E phospho-mimic mutant mice. This model rationalizes how basic mutations proximal to phosphotyrosines can restrict counter-regulation by phosphatases, providing new mechanismistic and treatment insights for 6000+ potentially relevant cancer mutations.


Assuntos
Proteínas Tirosina Fosfatases , beta Catenina , Animais , Camundongos , Mutação , Fosforilação , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Tirosina/metabolismo , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
20.
Org Lett ; 24(37): 6857-6862, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36074726

RESUMO

A Rh(III)-catalyzed [5+2] annulation of vinyl tyrosines with symmetrical and unsymmetrical internal alkynes was achieved, furnishing a series of oxepine-mounted tyrosine-based unnatural amino acids. In addition, the chemical applicability of the developed strategy was exemplified by stapling amino acid/peptide-appended alkynes with vinyl tyrosines and late stage functionalization of tyrosine-containing dipeptides and tripeptide with internal alkynes.


Assuntos
Ródio , Alcinos/química , Catálise , Dipeptídeos , Oxepinas , Peptídeos , Ródio/química , Tirosina
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