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1.
J Ethnopharmacol ; 300: 115702, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36099982

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM) theory, depression is an emotional disease, which is thought to be related to stagnation of liver qi and dysfunction of the spleen in transport. Xiaoyao San (XYS) is considered to have the effects of soothing liver-qi stagnation and invigorating the spleen. The spleen has the function to transport and transform nutrients. The liver has also termed the center of energy metabolism in the body. Therefore, exploring the antidepressant effects of XYS from the perspective of energy metabolism may reveal new findings. AIM OF THE STUDY: Glucose catabolism is an important part of energy metabolism. In recent years, several researchers have found that XYS can exert antidepressant effects by modulating abnormalities in glucose catabolism-related metabolites. The previous research of our research group found that the hippocampus glucose catabolism was disordered in depression. However, the antidepressant potential of XYS through modulating the disorders of hippocampal glucose catabolism and the specific metabolic pathways and targets of XYS action were still unknown. The aim of this study was to address the above scientific questions. MATERIALS AND METHODS: In this research, the CUMS (chronic unpredictable mild stress) model was used as the animal model of depression. The antidepressant effect of XYS was evaluated by behavioral indicators. The specific pathways and targets of XYS modulating the disorders of glucose catabolism in the hippocampus of CUMS rats were obtained by stable isotope-resolved metabolomics. Further, the isotope tracing results were also verified by molecular biology and electron transmission electron microscopy. RESULTS: The results demonstrated that XYS pretreatment could significantly improve the depressive symptoms induced by CUMS. More importantly, it was found that XYS could modulate the disorders of glucose catabolism in the hippocampus of CUMS rats. Stable isotope-resolved metabolomics and enzyme activity tests showed that Lactate dehydrogenase (LDH), Pyruvate carboxylase (PC), and Pyruvate dehydrogenase (PDH) were targets of XYS for modulating the disorders of glucose catabolism in the hippocampus of CUMS rats. The Succinate dehydrogenase (SDH) and mitochondrial respiratory chain complex V (MRCC-Ⅴ) were targets of XYS to improve abnormal mitochondrial oxidative phosphorylation in the hippocampus of CUMS rats. XYS was also found to have the ability to improve the structural damage of mitochondria and nuclei in the hippocampal caused by CUMS. CONCLUSIONS: This study was to explore the antidepressant effect of XYS from the perspective of glucose catabolism based on a strategy combining stable isotope tracing, molecular biology techniques, and transmission electron microscopy. We not only obtained the specific pathways and targets of XYS to improve the disorders of glucose catabolism in the hippocampus of CUMS rats, but also revealed the specific targets of the pathways of XYS compared with VLF.


Assuntos
Medicamentos de Ervas Chinesas , Succinato Desidrogenase , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Depressão/psicologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Glucose/farmacologia , Hipocampo/metabolismo , Isótopos/metabolismo , Isótopos/farmacologia , Lactato Desidrogenases/metabolismo , Metabolômica/métodos , Piruvato Carboxilase , Piruvatos/farmacologia , Ratos , Estresse Psicológico/tratamento farmacológico , Succinato Desidrogenase/metabolismo
2.
Mar Drugs ; 20(11)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36354983

RESUMO

Astaxanthin (AX) is a carotenoid that exerts potent antioxidant activity and acts in cell membranes and mitochondria, which consist of the bilayer molecules. Targeting mitochondria to ameliorate inflammatory diseases by regulating mitochondrial metabolism has become possible and topical. Although AX has been shown to have anti-inflammatory effects in various cells, the mechanisms are quite different. In particular, the role of AX on mitochondrial metabolism in macrophages is still unknown. In this study, we investigated the effect of AX on mitochondria-mediated inflammation and its mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. AX attenuated the mitochondrial O2- production and maintained the mitochondrial membrane potential, implying that AX preserved mitochondrial homeostasis to avoid LPS stimulation-induced mitochondrial dysfunction. Additionally, AX prevented the decrease in mitochondrial complexes I, II, and III, which were caused by LPS stimulation. Especially, AX inhibited the reduction in mitochondrial succinate dehydrogenase (SDH; complex II) activity and upregulated the protein and mRNA level of SDH complex, subunit B. Furthermore, AX blocked the IL-1ß expression by regulating the SDH-HIF-1α axis and suppressed the energy shift from an OXPHOS phenotype to a glycolysis phenotype. These findings revealed important effects of AX on mitochondrial enzymes as well as on mitochondrial energy metabolism in the immune response. In addition, these raised the possibility that AX plays an important role in other diseases caused by SDH mutation and metabolic disorders.


Assuntos
Lipopolissacarídeos , Succinato Desidrogenase , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/farmacologia , Mitocôndrias , Imunidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
3.
Nat Commun ; 13(1): 6107, 2022 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-36245043

RESUMO

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.


Assuntos
Autorrenovação Celular , Leucemia Mieloide Aguda , Humanos , Autorrenovação Celular/genética , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Succinato Desidrogenase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
J Agric Food Chem ; 70(43): 13839-13848, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36270026

RESUMO

A series of pyrazol-5-yl-benzamide derivatives containing the oxazole group were designed and synthesized as potential SDH inhibitors. According to the results of the bioassays, most target compounds displayed moderate-to-excellent in vitro antifungal activities against Valsa mali, Sclerotinia scleotiorum, Alternaria alternata, and Botrytis cinerea. Among them, compounds C13, C14, and C16 exhibited more excellently inhibitory activities against S. sclerotiorum than boscalid (EC50 = 0.96 mg/L), with EC50 values of 0.69, 0.26, and 0.95 mg/L, respectively. In vivo experiments on rape leaves and cucumber leaves showed that compounds C13 and C14 exhibited considerable protective effects against S. sclerotiorum than boscalid. SEM analysis indicated that compounds C13 and C14 significantly destroyed the typical structure and morphology of S. scleotiorum hyphae. In the respiratory inhibition effect assays, compounds C13 (28.0%) and C14 (33.9%) exhibited a strong inhibitory effect on the respiration rate of S. sclerotiorum mycelia, which was close to boscalid (30.6%). The results of molecular docking indicated that compounds C13 and C14 could form strong interactions with the key residues TRP O:173, ARG P:43, TYR Q:58, and MET P:43 of the SDH. Furthermore, the antifungal mechanism of these derivatives was demonstrated by the SDH enzymatic inhibition assay. These results demonstrate that compounds C13 and C14 can be developed into novel SDH inhibitors for crop protection.


Assuntos
Rhizoctonia , Succinato Desidrogenase , Succinato Desidrogenase/metabolismo , Antifúngicos/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Oxazóis/farmacologia , Benzamidas/farmacologia
5.
Int J Mol Sci ; 23(19)2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-36232604

RESUMO

Previous studies have shown that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) is involved in the regulation of several biological processes in cancer. In our previous study, we demonstrated a crucial function of PIKE-A in cancer energy metabolism by regulating pentose phosphate pathway (PPP) flux. However, whether PIKE-A regulates energy metabolism through affecting mitochondrial changes are poorly understood. In the present study, we show that PIKE-A promotes mitochondrial membrane potential, leading to increasing proliferation of glioblastoma cell. Mechanistically, PIKE-A affects the expression of respiratory chain complex Ⅱ succinate dehydrogenase A (SDHA), mediated by regulating the axis of STAT3/FTO. Taken together, these results revealed that inhibition of PIKE-A reduced STAT3/FTO/SDHA expression, leading to the suppression of mitochondrial function. Thus, our findings suggest the PIKE-A/STAT3/FTO/SDHA axis as promising anti-cancer treatment targets.


Assuntos
Glioblastoma , Proteínas Proto-Oncogênicas c-akt , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Succinato Desidrogenase/metabolismo
6.
Biochemistry (Mosc) ; 87(8): 752-761, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36171656

RESUMO

The Complex II family encompasses membrane bound succinate:quinones reductases and quinol:fumarate reductases that catalyze interconversion of succinate and fumarate coupled with reduction and oxidation of quinone. These enzymes are found in all biological genres and share a modular structure where a highly conserved soluble domain is bound to a membrane-spanning domain that is represented by distinct variations. The current classification of the complex II family members is based on the number of subunits and co-factors in the membrane anchor (types A-F). This classification also provides insights into possible evolutionary paths and suggests that some of the complex II enzymes (types A-C) co-evolved as the whole assembly. Origin of complex II types D and F may have arisen from independent events of de novo association of the conserved soluble domain with a new anchor. Here we analyze a recent structure of Mycobacterium smegmatis Sdh2, a complex II enzyme with two transmembrane subunits and two heme b molecules. This analysis supports an earlier hypothesis suggesting that mitochondrial complex II (type C) with a single heme b may have evolved as an assembled unit from an ancestor similar to M. smegmatis Sdh2.


Assuntos
Hidroquinonas , Succinato Desidrogenase , Benzoquinonas , Sítios de Ligação , Fumaratos/metabolismo , Heme/metabolismo , Quinonas/metabolismo , Succinato Desidrogenase/metabolismo , Ácido Succínico
7.
Eur J Med Res ; 27(1): 172, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076266

RESUMO

Pancreatic adenocarcinoma (PDAC) and lung cancer are expected to represent the most common cancer types worldwide until 2030. Under typical conditions, mitochondria provide the bulk of the energy needed to sustain cell life. For that inhibition of mitochondrial complex ΙΙ (CΙΙ) and ubiquinone oxidoreductase with natural treatments may represent a promising cancer treatment option. A naturally occurring flavonoid with biological anti-cancer effects is chyrsin. Due to their improved bioavailability, penetrative power, and efficacy, chitosan-chrysin nano-formulations (CCNPs) are being used in medicine with increasing frequency. Chitosan (cs) is also regarded as a highly versatile and adaptable polymer. The cationic properties of Cs, together with its biodegradability, high adsorption capacity, biocompatibility, effect on permeability, ability to form films, and adhesive properties, are advantages. In addition, Cs is thought to be both safe and economical. CCNPs may indeed be therapeutic candidates in the treatment of pancreatic adenocarcinoma (PDAC) and lung cancer by blocking succinate ubiquinone oxidoreductase.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Quitosana , Neoplasias Pulmonares , Nanopartículas , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão/tratamento farmacológico , Quitosana/farmacologia , Flavonoides , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Succinato Desidrogenase/metabolismo , Ubiquinona
8.
PLoS One ; 17(9): e0274478, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36178902

RESUMO

The neuroendocrine tumours paraganglioma and pheochromocytoma (PPGLs) are commonly associated with succinate dehydrogenase (SDH) gene variants, but no human SDH-related PPGL-derived cell line has been developed to date. The aim of this study was to systematically explore practical issues related to the classical 2D-culture of SDH-related human paragangliomas and pheochromocytomas, with the ultimate goal of identifying a viable tumour-derived cell line. PPGL tumour tissue/cells (chromaffin cells) were cultured in a variety of media formulations and supplements. Tumour explants and dissociated primary tumour cells were cultured and stained with a range of antibodies to identify markers suitable for use in human PPGL culture. We cultured 62 PPGLs, including tumours with confirmed SDHB, SDHC and SDHD variants, as well as several metastatic tumours. Testing a wide range of basic cell culture media and supplements, we noted a marked decline in chromaffin cell numbers over a 4-8 week period but the persistence of small numbers of synaptophysin/tyrosine hydroxylase-positive chromaffin cells for up to 99 weeks. In cell culture, immunohistochemical staining for chromogranin A and neuron-specific enolase was generally negative in chromaffin cells, while staining for synaptophysin and tyrosine hydroxylase was generally positive. GFAP showed the most consistent staining of type II sustentacular cells. Of the media tested, low serum or serum-free media best sustained relative chromaffin cell numbers, while lactate enhanced the survival of synaptophysin-positive cells. Synaptophysin-positive PPGL tumour cells persist in culture for long periods but show little evidence of proliferation. Synaptophysin was the most consistent cell marker for chromaffin cells and GFAP the best marker for sustentacular cells in human PPGL cultures.


Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/patologia , Cromogranina A/metabolismo , Meios de Cultura Livres de Soro , Mutação em Linhagem Germinativa , Humanos , Lactatos , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/patologia , Fosfopiruvato Hidratase/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Sinaptofisina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Food Funct ; 13(20): 10525-10534, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36149397

RESUMO

Dihydromyricetin (DHM) has attracted wide concern for its excellent biological function and pharmacological activities and was reported to have a positive effect on skeletal muscle insulin resistance, slow-twitch fibers expression and AMPK signaling. Thus, we took porcine myotubes derived from skeletal muscle satellite cells as the object to investigate the effects of DHM on myosin heavy chain (MyHC) expression and its mechanism in this study. Data showed that DHM up-regulated protein expression of MyHC I and down-regulated the protein expression of MyHC IIb, accompanied by an increase of MyHC I mRNA level and a decrease of MyHC IIb mRNA level. Besides, DHM increased the activities of malate dehydrogenase and succinic dehydrogenase and reduced lactate dehydrogenase activity. AMP-activated protein kinase (AMPK) was phosphorylated and AMPKα1 mRNA level was increased by DHM. The AMPK signaling-related factors including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), sirtuin1 (Sirt1), nuclear respiratory factor 1 (NRF1), and phospho-calmodulin-dependent protein kinase kinase-ß (p-CaMKKß) were increased by DHM. Inhibition of the AMPK signaling by compound C and AMPKα1 siRNA significantly attenuated the effects of DHM on expressions of MyHC I, MyHC IIb, PGC-1α and Sirt1. As a whole, DHM increased MyHC I expression and decreased MyHC IIb expression by the AMPK signaling.


Assuntos
Proteínas Quinases Ativadas por AMP , Cadeias Pesadas de Miosina , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Flavonóis , Lactato Desidrogenases/metabolismo , Malato Desidrogenase/metabolismo , Malato Desidrogenase/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/farmacologia , Suínos
10.
J Biol Chem ; 298(10): 102472, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36089066

RESUMO

The membrane-bound complex II family of proteins is composed of enzymes that catalyze succinate and fumarate interconversion coupled with reduction or oxidation of quinones within the membrane domain. The majority of complex II enzymes are protein heterotetramers with the different subunits harboring a variety of redox centers. These redox centers are used to transfer electrons between the site of succinate-fumarate oxidation/reduction and the membrane domain harboring the quinone. A covalently bound FAD cofactor is present in the flavoprotein subunit, and the covalent flavin linkage is absolutely required to enable the enzyme to oxidize succinate. Assembly of the covalent flavin linkage in eukaryotic cells and many bacteria requires additional protein assembly factors. Here, we provide mechanistic details for how the assembly factors work to enhance covalent flavinylation. Both prokaryotic SdhE and mammalian SDHAF2 enhance FAD binding to their respective apoprotein of complex II. These assembly factors also increase the affinity for dicarboxylates to the apoprotein-noncovalent FAD complex and stabilize the preassembly complex. These findings are corroborated by previous investigations of the roles of SdhE in enhancing covalent flavinylation in both bacterial succinate dehydrogenase and fumarate reductase flavoprotein subunits and of SDHAF2 in performing the same function for the human mitochondrial succinate dehydrogenase flavoprotein. In conclusion, we provide further insight into assembly factor involvement in building complex II flavoprotein subunit active site required for succinate oxidation.


Assuntos
Flavoproteínas , Succinato Desidrogenase , Humanos , Succinato Desidrogenase/metabolismo , Flavoproteínas/química , Flavina-Adenina Dinucleotídeo/metabolismo , Flavinas/metabolismo , Ácido Succínico , Apoproteínas/metabolismo , Fumaratos
11.
Aquat Toxicol ; 252: 106282, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36150281

RESUMO

Quinone outside inhibitor fungicides (QoIs) and succinate dehydrogenase inhibitor fungicides (SDHIs) were classified as highly or moderately toxic to nontarget aquatic organisms, which deterred their application in paddy scenario. Currently, the mechanism of toxicity regarding which factors govern their risk ranking in fish species are not fully explored. In this study, adult zebrafish were exposed to four QoIs (pyraclostrobin, trifloxystrobin, kresoxim-methyl, and azoxystrobin) and three SDHIs (isopyrazam, thifluzamide, and boscalid) to assess its acute toxicity and effects on tissue accumulation and gill injury. The results showed that the overall toxicity level was in the order of QoIs > SDHIs, whereas the order of accumulation capacity was SDHIs > QoIs. Seven mitochondrial respiratory inhibitors exposure induced serious histological damage in the gills, including aneurism, curling, telangiectasia and swelling, and caused mitochondrial dysfunction and weaker complex II and III activities. The correlation between their acute toxicities and in vitro gill cytotoxicity was significant (R = 0.868), whereas the bioaccumulation level was not markedly associated with their 96h-LC50 values in zebrafish (R = -0.686), indicating the degree of target organ (gill) injury may be the decisive factor that governs the risk grade of respiratory inhibitors in fish. Additionally, the docking positions and binding energies of fungicides with the target proteins may be responsible for their differential branchial damage. These results offer a point of reference and theoretical support for the design of fungicides and appropriate formulations with improved environmental safety that could broaden their application scenario.


Assuntos
Fungicidas Industriais , Poluentes Químicos da Água , Animais , Estrobilurinas/toxicidade , Peixe-Zebra/metabolismo , Succinato Desidrogenase/metabolismo , Fungicidas Industriais/metabolismo , Poluentes Químicos da Água/toxicidade
12.
Physiol Rep ; 10(18): e15478, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36117307

RESUMO

Type 2 diabetes mellitus (T2DM) is characterized by reduced exercise tolerance due to increased fatigability in skeletal muscle. In this study, we investigated muscle fatigue resistance of soleus (SOL) muscle in obese type 2 diabetic model mice (db/db). No differences in muscle volume, absolute force, or specific force in SOL muscle were observed between db/db mice and control mice (db/+), while fatigue resistance evaluated by repeated tetanic contractions was significantly lower in db/db mice (30th tetani, db/+: 63.7 ± 4.7%, db/db: 51.3 ± 4.8%). The protein abundance related to Ca2+ release from the sarcoplasmic reticulum (SR) in SOL muscle was not different between db/db mice and db/+ mice, while SR Ca2+ -ATPase (Ca2+ reuptake to SR) protein was decreased in db/db mice compared to db/+ mice (db/+: 1.00 ± 0.17, db/db: 0.60 ± 0.04, relative units). In addition, mitochondrial oxidative enzyme activity (succinate dehydrogenase) was decreased in the SOL muscle of db/db mice (p < 0.05). These data suggest that fatigue resistance in slow-twitch dominant muscle is impaired in mice with T2DM. Decreased mitochondrial oxidative enzyme activity and impairment of Ca2+ uptake to SR, or both might be involved in the mechanisms.


Assuntos
Diabetes Mellitus Tipo 2 , Retículo Sarcoplasmático , Animais , Camundongos , Camundongos Endogâmicos , Músculo Esquelético/metabolismo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Succinato Desidrogenase/metabolismo
13.
Curr Oncol ; 29(8): 5933-5941, 2022 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-36005206

RESUMO

Gastrointestinal stromal tumors (GISTs) account for 1% of GI neoplasms in adults, and epidemiological data suggest an even lower occurrence in pregnant women. The majority of GISTs are caused by KIT and PDGFRA mutations. This is not the case in women of childbearing age. Some GISTs do not have a KIT/PDGFRA mutation and are classified as wild-type (WT) GISTs. WT-GIST includes many molecular subtypes including SDH deficiencies. In this paper, we present the first case report of a metastatic SDH-deficient GIST in a 23-year-old pregnant patient and the challenges encountered given her concurrent pregnancy. Our patient underwent a surgical tumor resection of her gastric GIST as well as a lymphadenectomy a week after induction of labor at 37 + 1 weeks. She received imatinib, sunitinib as well as regorafenib afterward. These drugs were discontinued because of disease progression despite treatment or after side effects were reported. Hence, she is currently under treatment with ripretinib. Her last FDG-PET showed a stable disease. This case highlights the complexity of GI malignancy care during pregnancy, and the presentation and management particularities of metastatic WT-GISTs. This case also emphasizes the need for a multidisciplinary approach and better clinical guidelines for offering optimal management to women in this specific context.


Assuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Adulto , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Gravidez , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Adulto Jovem
14.
Biochim Biophys Acta Mol Basis Dis ; 1868(12): 166530, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36038039

RESUMO

Macrophages undergo extensive metabolic reprogramming during classical pro-inflammatory polarization (M1-like). The accumulation of itaconate has been recognized as both a consequence and mediator of the inflammatory response. In this study we first examined the specific functions of itaconate inside fractionated mitochondria. We show that M1 macrophages produce itaconate de novo via aconitase decarboxylase 1 (ACOD1) inside mitochondria. The carbon for this reaction is not only supplied by oxidative TCA cycling, but also through the reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase (IDH). While macrophages are capable of sustaining a certain degree of itaconate production during hypoxia by augmenting the activity of IDH-dependent reductive carboxylation, we demonstrate that sufficient itaconate synthesis requires a balance of reductive and oxidative TCA cycle metabolism in mouse macrophages. In comparison, human macrophages increase itaconate accumulation under hypoxic conditions by augmenting reductive carboxylation activity. We further demonstrated that itaconate attenuates reductive carboxylation at IDH2, restricting its own production and the accumulation of the immunomodulatory metabolites citrate and 2-hydroxyglutarate. In line with this, reductive carboxylation is enhanced in ACOD1-depleted macrophages. Mechanistically, the inhibition of IDH2 by itaconate is linked to the alteration of the mitochondrial NADP+/NADPH ratio and competitive succinate dehydrogenase inhibition. Taken together, our findings extend the current model of TCA cycle reprogramming during pro-inflammatory macrophage activation and identified novel regulatory properties of itaconate.


Assuntos
Carboxiliases , Ciclo do Ácido Cítrico , Isocitrato Desidrogenase , Succinatos , Aconitato Hidratase/metabolismo , Animais , Carbono/metabolismo , Carboxiliases/metabolismo , Citratos , Retroalimentação , Humanos , Ácidos Cetoglutáricos/metabolismo , Camundongos , NADP/metabolismo , Succinato Desidrogenase/metabolismo , Succinatos/metabolismo
15.
J Clin Endocrinol Metab ; 107(10): 2801-2810, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35948272

RESUMO

CONTEXT: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that are frequently associated with succinate dehydrogenase (SDH) germline mutations. When mutated, SDH losses its function, thus leading to succinate accumulation. OBJECTIVE: In this study, we evaluated serum succinate levels as a new metabolic biomarker in SDHx-related carriers. METHODS: Retrospective monocentric study of 88 PPGL patients (43 sporadic, 35 SDHB, 10 SDHA/C/D), 17 tumor-free familial asymptomatic carriers (13 SDHB, 4 SDHC/D), and 60 healthy controls. Clinical, biological, and imaging data were reviewed. Serum succinate levels (n = 280) were quantified by an ultra-performance liquid chromatography coupled to a tandem mass spectrometry method and correlated to SDHx mutational status, disease extension, and other biological biomarkers. RESULTS: Serum succinate levels > 7 µM allowed identification of tumor-free asymptomatic SDHB-mutated cases compared to a healthy control group (100% specificity; 85% sensitivity). At PPGL diagnosis, SDHB-mutated patients had a significantly increased median succinate level (14 µM) compared to sporadic patients (8 µM) (P < 0.01). Metastatic disease extension was correlated to serum succinate levels (r = 0.81). In the SDHB group, patients displaying highest tumor burdens showed significant increased succinate levels compared to the sporadic group (P < 0.0001). CONCLUSIONS: In this pilot study, we showed that serum succinate level is an oncometabolic biomarker that should be useful to identify SDHB-related carriers. Succinate levels are also a marker of metabolic tumor burden in patients with a metastatic PPGL and a potential marker of treatment response and follow-up.


Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Biomarcadores Tumorais/genética , Mutação em Linhagem Germinativa , Humanos , Mutação , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Projetos Piloto , Estudos Retrospectivos , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Ácido Succínico/metabolismo
16.
Cell Stress Chaperones ; 27(5): 573-585, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35976490

RESUMO

The molecular chaperone TNF-receptor-associated protein-1 (TRAP1) controls mitochondrial respiration through regulation of Krebs cycle and electron transport chain activity. Post-translational modification (PTM) of TRAP1 regulates its activity, thereby controlling global metabolic flux. O-GlcNAcylation is one PTM that is known to impact mitochondrial metabolism, however the major effectors of this regulatory PTM remain inadequately resolved. Here we demonstrate that TRAP1-O-GlcNAcylation decreases TRAP1 ATPase activity, leading to increased mitochondrial metabolism. O-GlcNAcylation of TRAP1 occurs following mitochondrial import and provides critical regulatory feedback, as the impact of O-GlcNAcylation on mitochondrial metabolism shows TRAP1-dependence. Mechanistically, loss of TRAP1-O-GlcNAcylation decreased TRAP1 binding to ATP, and interaction with its client protein succinate dehydrogenase (SDHB). Taken together, TRAP1-O-GlcNAcylation serves to regulate mitochondrial metabolism by the reversible attenuation of TRAP1 chaperone activity.


Assuntos
Chaperonas Moleculares , Succinato Desidrogenase , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Processamento de Proteína Pós-Traducional , Respiração , Succinato Desidrogenase/metabolismo , Fator 1 Associado a Receptor de TNF/química , Fator 1 Associado a Receptor de TNF/metabolismo
17.
J Hazard Mater ; 440: 129729, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35963089

RESUMO

Traditional risk assessment of pesticide concludes at the racemic level, which is often incomprehensive. In this study, systematic studies on environmental stability, bioactivity, and ecotoxicological effects of fungicide penflufen were carried out at the enantiomeric level. The single-enantiomer of penflufen was successfully separated and prepared, and their stability was verified in different environmental matrices. Meanwhile, bioactivity test indicated that S-(+)-penflufen had increased bioactivity with its bioactivities against Rhizoctonia solani, Fusarium oxysporum, and Fusarium moniliforme being factors of 7.8, 1.8, and 4.7, respectively greater than those of R-(-)-penflufen. Molecular docking results showed the strong hydrogen bond interactions with Leu300, enantiomer-specific hydrophobic interactions with Cys299, Arg91, and His93, and the greater binding energy between S-(+)-penflufen and succinate dehydrogenase of Rhizoctonia solani caused the selective bioactivity. Additionally, two enantiomers showed low acute toxicity whereas selective sub-chronic toxicity to earthworms. In sub-chronic toxicity test, the accumulated enantiomers caused abnormalities in intestinal tract structure, enzyme activities, and gene expression of earthworms, especially in the S-(+)-penflufen treatment. The selective interactions between penflufen enantiomers and key proteins were elucidated using molecular docking, which may be the main reason of stereoselective subchronic toxicity. S-(+)-penflufen has high bioactivity and low acute risk, it has great potential for development.


Assuntos
Fungicidas Industriais , Oligoquetos , Praguicidas , Anilidas , Animais , Fungicidas Industriais/química , Simulação de Acoplamento Molecular , Oligoquetos/metabolismo , Rhizoctonia , Estereoisomerismo , Succinato Desidrogenase/metabolismo , Transcriptoma
18.
Ultrason Sonochem ; 89: 106111, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35998484

RESUMO

Lyophyllum decastes is a common mushroom that is prone to browning during prolonged storage. In this study, the effects of ultrasonic treatment on metabolic gene expression, enzyme activity, and metabolic compounds related to L. decastes browning were investigated. Treatment of the fruiting body at 35 kHz and 300 W for 10 min reduced the browning index of L. decastes by 21.0 % and increased the L* value by 11.1 %. Ultrasonic treatment of the fruiting body resulted in higher levels of total phenols, flavonoids, and 9 kinds of amino acid with catalase (CAT) and peroxidase (POD) activities maintained at high levels. Higher cytochrome c oxidase (CCO), succinate dehydrogenase (SDH), phosphofructokinase (PFK), and pyruvate kinase (PK) activities may be ascribed to increased antioxidant capacity. Moreover, ultrasonication retained higher adenosine triphosphate (ATP) concentrations with an increased energy charge, while there were lower levels of adenosine diphosphate (ADP) and reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+), respectively. Meanwhile, lower lignin contents were observed, along with retarded polyphenol oxidase (PPO) and lipoxygenase (LOX) activities. Lower PPO activity reduced the fruiting body enzymatic browning rate through decreased expression of LdPpo1, LdPpo2, and LdPpo3 during storage at 4 °C for 16 days. This activity may be used to determine the effectiveness of ultrasonication.


Assuntos
NAD , Succinato Desidrogenase , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Agaricales , Aminoácidos/metabolismo , Antioxidantes/metabolismo , Catalase/metabolismo , Catecol Oxidase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético , Flavonoides , Lignina/metabolismo , Lipoxigenases/metabolismo , NAD/metabolismo , Fenóis/química , Fosfofrutoquinases/metabolismo , Piruvato Quinase/metabolismo , Succinato Desidrogenase/metabolismo , Ultrassom
19.
Sci Total Environ ; 851(Pt 1): 158176, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-35995159

RESUMO

As a good carrier of contaminants, nanotitanium dioxide (nTiO2) can absorb organic pollutants, producing toxicological effects on organisms. However, the complex effects of nTiO2 with contaminants on marine mussels are still unclear. In this study, we exposed mussels to tris (2-chloropropyl) phosphate (TCPP) 100 µg/L (T1), 0.5 mg/L nTiO2 + 100 µg/L TCPP (T2), 1.0 mg/L nTiO2 + 100 µg/L TCPP (T3) and control (0 nTiO2 + 0 µg/L TCPP) treatments, and assessed the combined effects of TCPP with nTiO2 on the thick-shelled mussel Mytilus coruscus by detecting the activities of gill pyruvate kinase (PK), hexokinase (HK), lactate dehydrogenase (LDH) and succinate dehydrogenase (SDH), also gill acetylcholine (Ach) and muscle lactic acid (LD) contents and gut microbiota after 14-d exposure. Compared with the control group, PK activity was increased significantly, but SDH, LDH activities and LD content were decreased significantly in T1, with the addition of nTiO2, there were not significantly different in T3. However, Ach content in T3 was significantly higher than the control and T1. Moreover, KEGG of the gut microbiota via 16 s rRNA sequencing showed that most pathways returned to the control level in T3. The results showed that TCPP affected the respiratory metabolism of mussels, changed the community structure of intestinal microflora in mussels, and nTiO2 alleviated the toxicity of TCPP. Our study provides new insights for ecological risk assessment of TCPP in bivalves in the complex aquatic environment and the novel role of nTiO2 in regulating the toxicity of TCPP.


Assuntos
Microbioma Gastrointestinal , Mytilus , Poluentes Químicos da Água , Acetilcolina , Animais , Hexoquinase/metabolismo , Lactato Desidrogenases/metabolismo , Ácido Láctico , Mytilus/metabolismo , Fosfatos/metabolismo , Porfirinas , Piruvato Quinase/metabolismo , Succinato Desidrogenase/metabolismo , Titânio/química , Poluentes Químicos da Água/análise
20.
Int J Mol Sci ; 23(16)2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36012366

RESUMO

Human microbiota produces metabolites that may enter the bloodstream and exert systemic influence on various functions including mitochondrial. Mitochondria are not only a target for microbial metabolites, but also themselves, due to the inhibition of several enzymes, produce metabolites involved in infectious processes and immune response. The influence of indolic acids, microbial derivatives of tryptophan, as well as itaconic acid, formed in the tricarboxylic acid cycle under the action of bacterial lipopolysaccharides, on the activity of mitochondrial enzymes was studied by methyl thiazolyl tetrazolium (MTT), dichlorophenolindophenol (DCPIP) and pyridine nucleotide fluorescence assays. Thus, it was found that indolic acids suppressed succinate and glutamate oxidation, shifting the redox potential of pyridine nucleotides to a more oxidized state. Itaconic acid, in addition to the well-known inhibition of succinate oxidation, also decreased NAD reduction in reactions with glutamate as a substrate. Unlike itaconic acid, indolic acids are not direct inhibitors of succinate dehydrogenase and glutamate dehydrogenase as their effects could be partially eliminated by the thiol antioxidant dithiothreitol (DTT) and the scavenger of lipid radicals butyl-hydroxytoluene (BHT). Alkalization turned out to be the most effective means to decrease the action of these metabolites, including itaconic acid, which is due to the protective influence on redox-dependent processes. Thus, among mitochondrial oxidative enzymes, the most accessible targets of these microbial-related metabolites are succinate dehydrogenase and glutamate dehydrogenase. These are important in the context of the shifting of metabolic pathways involved in bacterial inflammation and sepsis as well as the detection of new markers of these pathologies.


Assuntos
Glutamato Desidrogenase , Succinato Desidrogenase , Glutamato Desidrogenase/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Inflamação/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Piridinas/metabolismo , Succinato Desidrogenase/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia , Ácido Succínico/metabolismo
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