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1.
Artigo em Russo | MEDLINE | ID: mdl-38529859

RESUMO

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting¼ of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.


Assuntos
Meglumina/análogos & derivados , Succinatos , Ácido Succínico , Humanos , Ácido Succínico/uso terapêutico , Succinatos/uso terapêutico , Picolinas/uso terapêutico , Piridinas/uso terapêutico
2.
Endocrinol Metab (Seoul) ; 38(4): 395-405, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37533177

RESUMO

BACKGRUOUND: Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study. METHODS: In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver. RESULTS: Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis. CONCLUSION: Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.


Assuntos
Floretina , Ácido Succínico , Camundongos , Animais , Ácido Succínico/metabolismo , Ácido Succínico/farmacologia , Ácido Succínico/uso terapêutico , Floretina/farmacologia , Floretina/metabolismo , Floretina/uso terapêutico , Células Estreladas do Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle
3.
J Ethnopharmacol ; 317: 116675, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37257708

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory injury is an important pathological factor for the formation of atherosclerotic plaque. It is well known that Puerarin and Tanshinone IIA (Pue-Tan) can significantly reduce interleukin-1ß (IL-1ß) levels and delay the atherosclerosis (AS) process clinically in China. Previous evidence has shown that the Succinate/HIF-1α/IL-1ß inflammatory signaling axis (Succinate axis) promotes the progression of atherosclerotic inflammatory plaques. It is not clear whether Pue-Tan inhibits inflammatory plaques by reducing the level of IL-1ß through the succinate signaling axis. AIM OF STUDY: Find out the interaction between Pue-Tan targets and the succinate axis by means of network pharmacology and bioinformatics analysis and to further confirm whether Pue-Tan can inhibit vascular inflammation and delay the formation of atherosclerotic inflammatory plaques by targeting the succinate signaling axis. MATERIALS AND METHODS: Firstly, animal experiments were conducted to verify the changing relationship between Succinate and IL-1ß under Pue-Tan intervention. Secondly, network pharmacology approach was employed to uncover the specific targets of Pue-Tan in the intervention of AS from multiple levels of components, proteins, and pathways, and at the same time, the target must be a key factor of the succinate signaling axis. Autodock vina1.5.6 was applied to molecular docking for Pue-Tan and target protein. Subsequently, cells experiment and animal experiment were performed to verify Pue-Tan inhibiting the inflammatory progression of atherosclerosis by targeting succinate signaling axis. RESULTS: Firstly, we first found that the reduction of IL-1ß was positively correlated with succinate in the serum of Pue-Tan-treated mice. Secondly, network pharmacology compared with molecular docking showed that hypoxia-induced factor-1α (HIF-1α) was the key target of Pue-Tan and the key node of succinate singling axis. Finally, in vitro study, Pue-Tan significantly reduced the factors of succinate axis just as HIF-1α siRNA; in vivo study, we confirmed a decreased expression of succinate axis and ICAM-1 in the aorta of ApoE-/- mice under Pue-Tan intervention, which was consistent with the in vitro results. CONCLUSION: This study confirmed that Pue-Tan blocked the succinate axis by targeting HIF-1α to prevent the formation of atherosclerotic inflammatory plaques and delay the pathological process of AS. Network Pharmacology, Bioinformatics of Molecular Docking, and Molecular Biology Validation can be used as a effective way to discover and verify the pharmacological mechanism of TCM.


Assuntos
Aterosclerose , Placa Aterosclerótica , Camundongos , Animais , Placa Aterosclerótica/tratamento farmacológico , Ácido Succínico/uso terapêutico , Interleucina-1beta , Simulação de Acoplamento Molecular , Aterosclerose/metabolismo , Hipóxia , Succinatos
4.
Am J Physiol Endocrinol Metab ; 324(3): E226-E240, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36724126

RESUMO

Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction.NEW & NOTEWORTHY Exogenous succinate induces major changes in brown adipose tissue protein expression affecting particularly mitochondrial respiration and structural proteins. When given exogenously in drinking water, succinate mitigates body mass gain in a rodent model of diet-induced obesity; in addition, when given in association with the glucagon-like peptide-1 receptor agonist, liraglutide, succinate increases body mass reduction promoted by liraglutide alone.


Assuntos
Tecido Adiposo Marrom , Liraglutida , Animais , Camundongos , Tecido Adiposo Marrom/metabolismo , Metabolismo Energético , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Obesidade/metabolismo , Proteoma/metabolismo , Ácido Succínico/farmacologia , Ácido Succínico/metabolismo , Ácido Succínico/uso terapêutico , Termogênese , Proteína Desacopladora 1/metabolismo
5.
Signal Transduct Target Ther ; 8(1): 41, 2023 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681678

RESUMO

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.


Assuntos
Cálculos Renais , Urolitíase , Animais , Ratos , Ácido Succínico/uso terapêutico , Osteogênese , Urolitíase/metabolismo , Cálculos Renais/tratamento farmacológico , Cálculos Renais/genética , Cálculos Renais/química , Succinatos/uso terapêutico
6.
J Ethnopharmacol ; 303: 116007, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36473618

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xianglian pill (XLP), a traditional Chinese formula, is widely used as treatment for ulcerative colitis (UC) in China. However, the mechanism of its therapeutic effect is still unclear. AIM OF THE STUDY: Our previous studies showed a low oral bioavailability and a predominant distribution of major XLP ingredients in the gut. In the present study, we aimed to explore the mechanism of action of XLP on UC with respect to the regulation of gut microecology. MATERIALS AND METHODS: UC model rats established using 5% dextran sulfate sodium were treated with XLP. After the treatment period, bodyweight, colon length, histopathology, and inflammatory changes were evaluated. Further, changes in gut microbiota structure were detected via 16S rRNA sequencing, and microbial metabolites in feces were analyzed via a metabolomic assay. Antibiotic intervention and fecal microbiota transplantation were also employed to explore the involvement of gut microbiota, while the level of regulatory T cells (Tregs) in mesenteric lymph nodes was determined via flow cytometry. Transcriptome sequencing was also performed to determine colonic gene changes. RESULTS: XLP alleviated colonic injury, inflammation, and gut microbial dysbiosis in UC model rats and also changed microbial metabolite levels. Particularly, it significantly decreased succinate level in the tyrosine pathway. We also observed that fecal microbiota derived from XLP-treated rats conferred resilience to UC model rats. However, this therapeutic effect of XLP on UC was inhibited by succinate. Moreover, XLP increased the level of anti-inflammatory cellular Tregs via gut microbiota. However, this beneficial effect was counteracted by succinate supplementation. Further, XLP induced the differentiation of Treg possibly by the regulation of the PHD2/HIF-1α pathway via decreasing microbial succinate production. CONCLUSIONS: Our findings indicated that XLP exerts its therapeutic effects on UC mainly via the gut microbiota-succinate-Treg differentiation axis.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Ratos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Linfócitos T Reguladores , Ácido Succínico/metabolismo , Ácido Succínico/farmacologia , Ácido Succínico/uso terapêutico , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Colo , Succinatos/farmacologia , Sulfato de Dextrana/toxicidade , Colite/tratamento farmacológico , Modelos Animais de Doenças
7.
Artigo em Inglês | MEDLINE | ID: mdl-35680173

RESUMO

INTRODUCTION: Antioxidants may have positive impact on diabetic polyneuropathy (DPN), presumably due to alleviation of oxidative stress. We aimed to evaluate the efficacy and safety of combination of antioxidants: succinic acid, inosine, nicotinamide, and riboflavin (SINR) in the treatment of DPN. RESEARCH DESIGN AND METHODS: In a double-blind, placebo-controlled clinical trial, men and women aged 45-74 years with type 2 diabetes and symptomatic DPN, with initial Total Symptom Score (TSS) ˃5, were randomized into experimental (n=109) or placebo (n=107) group. Patients received study medication/placebo intravenously for 10 days, followed by oral administration for 75 days. Statistical significance was defined as a two-tailed p<0.05. RESULTS: In SINR group, mean TSS change after 12 weeks was -2.65 (±1.46) vs -1.73 (±1.51) in the placebo group (p<0.0001; t-test). Reduction of symptoms in the SINR group was achieved regardless of hemoglobin A1c levels, but better results were observed in patients with initial TSS <7.5. The analysis of TSS subscores revealed statistically significant between-group differences by dynamics of the intensity of paresthesia and of numbness starting from day 11 (p=0.035 and p=0.001, respectively; mixed model); by day 57, statistically significant between-group differences were detected also by dynamics of burning intensity (p=0.005; mixed model). Study limitations are small effect size, moderate proportion of patients with severe DPN symptoms, subjective assessment of outcomes, exclusion of participants who received injectable glucose-lowering medications other than insulins, and patients with uncontrolled and type 1 diabetes. CONCLUSIONS: The combination of SINR effectively alleviates DPN symptoms in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04649203; Unique Protocol ID: CTF-III-DM-2019).


Assuntos
Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Feminino , Humanos , Masculino , Antioxidantes/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Inosina/uso terapêutico , Niacinamida/efeitos adversos , Riboflavina/efeitos adversos , Ácido Succínico/uso terapêutico
8.
EMBO J ; 41(12): e108306, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35506364

RESUMO

Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Infecções por Orthomyxoviridae , Pneumonia , Animais , Antivirais/farmacologia , Humanos , Vírus da Influenza A Subtipo H3N2/metabolismo , Camundongos , Proteínas do Nucleocapsídeo , Nucleoproteínas/metabolismo , Ácido Succínico/metabolismo , Ácido Succínico/farmacologia , Ácido Succínico/uso terapêutico , Replicação Viral
9.
Ter Arkh ; 93(12): 1470-1476, 2021 Dec 15.
Artigo em Russo | MEDLINE | ID: mdl-36286675

RESUMO

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.


Assuntos
Colestase Intra-Hepática , S-Adenosilmetionina , Humanos , Fosfatase Alcalina/uso terapêutico , Bilirrubina/uso terapêutico , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/tratamento farmacológico , gama-Glutamiltransferase/uso terapêutico , Inosina/uso terapêutico , Meglumina/efeitos adversos , Metionina , Niacinamida/uso terapêutico , S-Adenosilmetionina/farmacologia , Ácido Succínico/uso terapêutico , Transaminases/uso terapêutico
10.
Neurourol Urodyn ; 40(1): 120-130, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098175

RESUMO

AIM: Succinate activates the receptor GPR91 identified in the bladder. The present study aims to unravel the mechanisms of bladder relaxation by succinate and how the receptor is involved in structural and functional changes of the bladder. METHODS: Physiological recordings of bladder function were carried out by cystometry and organ bath from C57BL/6 mice, homozygous GPR91-/- mice, and Sprague-Dawley (SD) rats. GPR91 expression was confirmed by polymerase chain reaction and tissue morphology was examined by light (Masson trichrome) and fluorescence microscopy. Nitric oxide (NO) and ATP secretion were measured. RESULTS: Bladders of GPR91 KO mice had a greater mass to body weight ratio with a thicker bladder wall compared to C57BL/6 mice. They also displayed increased basal and maximal bladder pressures, and decreased intercontraction intervals, bladder capacity, micturition volume, and compliance. During cystometry, bladders of SD rats and C57BL/6 mice instilled with succinate (10 mM) showed signs of relaxation while bladders of GPR91 KO mice were unresponsive. Similarly, in organ bath, succinate relaxed bladder strips preincubated with carbachol, except GPR91 KO ones. Relaxation was stronger in the presence of urothelium and independent of NO synthesis. Bladder strips from all mice groups showed similar responses to KCl, carbachol, and electrical stimulation. In vitro, succinate increased NO secretion in urothelial cell culture of both C57BL6 and GPR91 KO mice while ATP secretion was potently decreased by succinate in C57BL6 culture only. CONCLUSION: Succinate through GPR91 is essential to bladder structure and contraction. GPR91 relaxes the detrusor partially by decreasing urothelial ATP secretion.


Assuntos
Receptores Acoplados a Proteínas G/metabolismo , Ácido Succínico/uso terapêutico , Doenças da Bexiga Urinária/tratamento farmacológico , Micção/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Ácido Succínico/farmacologia
11.
Ann Clin Transl Neurol ; 8(1): 252-258, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33231368

RESUMO

SUCLA2 is a component of mitochondrial succinate-CoA ligase and nucleotide diphosphokinase activities. Its absence results in Krebs cycle failure, mitochondrial DNA depletion, and a childhood-fatal encephalomyopathy. We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade. We show that succinate supplementation circumvents the Krebs cycle block, but does not correct the neurologic disease. Our patients' Arg407Trp mutation has been reported in children with (yet) no MRI abnormalities. It remains possible that early succinate supplementation could impact the disease.


Assuntos
Surdez/genética , Transtornos dos Movimentos/genética , Succinato-CoA Ligases/genética , Surdez/tratamento farmacológico , Feminino , Humanos , Masculino , Transtornos dos Movimentos/tratamento farmacológico , Mutação de Sentido Incorreto , Linhagem , Ácido Succínico/uso terapêutico
12.
Arch Med Res ; 52(3): 270-276, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33199038

RESUMO

BACKGROUND AND AIMS: Although several treatment regimens for T-cell acute lymphoblastic leukemia (T-ALL), trouble is still ongoing that relapse of disease after therapies in both pediatric and adult patients. Hence, the demand for new alternative therapeutics that are antiproliferative for cancer cells but do not harm healthy cells in treatments is increasing day by day. This study aimed to investigate whether succinic acid show anti-proliferative and apoptotic effect of on T-ALL cell lines. METHODS: Time and dose-dependent effects of succinic acid on T-ALL cell lines were determined by using WST-1, caspase-3/ bicinchoninic acid (BCA), and Annexin V-Fluorescein isothiocyanate (FITC) assays. We included the MRC-5 cell line in our study as a healthy control group. RESULTS: Based on our findings, 25 and 50 mmol dosages of succinic acid has shown an apoptotic effect on T-ALL cell lines for 48 h treatment. Also, it has shown that after 48 h exposure of 25 and 50 mmol dosages of succinic acid has no significant cytotoxic effect in healthy MRC-5 cells. Apoptotic activity of succinic acid on CCRF-CEM cell line was caspase-3 dependent but not for MOLT-4. As a consequence, succinic acid was found to effect for T-ALL treatment in vitro and might also enlighten new study fields for different cancer experiments.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Ácido Succínico/uso terapêutico , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Ácido Succínico/farmacologia
13.
Br J Haematol ; 189(3): 442-451, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31883112

RESUMO

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.


Assuntos
Polietilenoglicóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Ácido Succínico/uso terapêutico , Feminino , Humanos , Masculino , Polietilenoglicóis/farmacologia , Ácido Succínico/farmacologia
14.
Cell Death Dis ; 9(7): 756, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988033

RESUMO

Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET-miR200-Zeb1/CtBP1-MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/metabolismo , Inibidores Enzimáticos/uso terapêutico , Complexo Cetoglutarato Desidrogenase/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Ácido Succínico/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ácido Succínico/química
15.
Cell Mol Biol (Noisy-le-grand) ; 64(1): 60-63, 2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29412795

RESUMO

Endometrium cancer is the most common invasive gynecologic malignancy in developed countries. Succinic acid (CO2HCH2-CH2CO2H) is a type of dibasic acid that has uncolored crystal. Succinic acid is used in bakery products and aromatized products. It is naturally found in some vegetables. Succinic acid has no adverse effects because it is metabolized by body cells and has a role in the tricarboxylic acid cycle (TCA) as a cycle media component. The TCA cycle and its enzyme components have some crucial roles for basal cell metabolism. Any mistakes, concentration differences in product, or enzyme deficiencies are important within the cell this cycle. In this proposal project, we aimed to investigate the effect of succinic acid at different doses and at different times in an endometrial cancer cell line. The study was performed using methods that determine for apoptosis (for cytotoxicity, WST-1, for caspase enzyme activity, Caspase 3/BCA; apoptotic determination using flow cytometry; Annexin V; to understand mitochondrial membrane potential; JC-1). The results showed that 5 and 10 µM concentration of succinic acid resulted in apoptosis in endometrium cancer; no such effect was seen in the control cell line, which comprised healthy lung cells.  According to our results, it is thought that succinic acid would be effective for the treatment of endometrial cancer cell lines, thus providing new data for other areas of cancer research.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Endométrio/tratamento farmacológico , Ácido Succínico/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/fisiopatologia , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/fisiopatologia , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Succínico/uso terapêutico
16.
Zh Nevrol Psikhiatr Im S S Korsakova ; 118(12. Vyp. 2): 64-69, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30830119

RESUMO

AIM: To determine the efficacy of post-stroke dysphagia treatment by choline alfoscerate (ChA), succinate combination (SC), and their combination with sip, larynx, and swallowing exercises. MATERIAL AND METHODS: Four groups of primary ischemic stroke (IS) patients (n=80; 62±0.2 y.o., verified by MRI), including controls, admitted to Stroke Unit 24 h after stroke in the area of RAM (29.5%), and LAM (70.5%), were studied. Basic therapy was provided according to National Stroke Treatment Recommendations, treated groups received ChA 14 mg/kg (2st gr.), SC 0.5 mg/kg (3nd gr.), combination of two compounds (3d gr.). Controls (4th gr.) received placebo. Pharmacological treatment was provided for 10 days with continuation by oral administration. Dysphagia was measured semi-quantitively by MASA scale, three scale determinants were measured on admission, on 5 and 13 days of stay in the hospital. RESULTS AND CONCLUSION: The differences were significant and observed on the 5th day of treatment. ChA mostly improved sip control, and larynx movements (38% above controls; p<0.01), while SC improved the closure of vocal cords (55% above controls; p<0.01). This may reflect the differences in synaptic control of these functions. Combined treatment was more effective than monotherapy: 15% above ChA, and 21% above SC for swallowing function (p=0.01); 33 and 22% for vocal closure, 37% (p=0.05) and 76% (p=0.01) for larynx movement, which may be due to synergism between two medications. Therefore, sip, larynx, and swallowing exercises with pharmacological support of ChA and SC ameliorated dysphagia after IS.


Assuntos
Isquemia Encefálica , Transtornos de Deglutição , Glicerilfosforilcolina , Acidente Vascular Cerebral , Ácido Succínico , Isquemia Encefálica/complicações , Deglutição , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/etiologia , Glicerilfosforilcolina/uso terapêutico , Humanos , Acidente Vascular Cerebral/complicações , Ácido Succínico/uso terapêutico
17.
Klin Khir ; (7): 55-7, 2015 Jul.
Artigo em Ucraniano | MEDLINE | ID: mdl-26591223

RESUMO

The results of examination and treatment of 231 patients on defects covering tissues of the trunk and limbs were presented. The severity of the injury determined by classification A. V. Kaplan, O. M. Markova. In 10 patients wound treatment method used, developed in the clinic, using the combined preparation of hyaluronic acid with sodium succinate (Latsert), ensuring efficiency of treatment. Differentiated approach to the selection of closing wound surfaces method caused by mechanical damage, allowed to achieve satisfactory results in 97.84% of cases.


Assuntos
Extremidades/cirurgia , Ácido Hialurônico/uso terapêutico , Ácido Succínico/uso terapêutico , Tronco/cirurgia , Ferimentos Penetrantes/tratamento farmacológico , Ferimentos Penetrantes/cirurgia , Adulto , Idoso , Extremidades/lesões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tronco/lesões , Resultado do Tratamento , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia , Ferimentos Penetrantes/patologia
18.
Artigo em Russo | MEDLINE | ID: mdl-26120981

RESUMO

OBJECTIVE: To study the dynamics of neurological and emotional disturbances in patients with dorsopathy treated with cytoflavin. MATERIAL AND METHODS: We examined 120 patients aged from 21 to 55 years, mean age 38±9 years. All patients received nonsteroid anti-inflammatory drugs, myorelaxants, vitamins. The main group comprised 67 patients who received cytoflavin (10ml of the solution in one injection once a day in 200 ml of isotonic solution of sodium chloride intravenously in drops in the morning during 10 days) in addition to standard treatment. The comparison group included 53 patients who received standard treatment during 10 days. RESULTS AND CONCLUSION: The use of cytoflavin allowed earlier arresting of the pain syndrome, restored the disturbed sensitivity, improved emotional status and decreased the severity of a neuropathic pain component.


Assuntos
Sintomas Afetivos/diagnóstico , Mononucleotídeo de Flavina/uso terapêutico , Inosina Difosfato/uso terapêutico , Dor Lombar/tratamento farmacológico , Niacinamida/uso terapêutico , Succinatos/uso terapêutico , Ácido Succínico/uso terapêutico , Adulto , Sintomas Afetivos/etiologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Dor Lombar/complicações , Dor Lombar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/uso terapêutico , Adulto Jovem
19.
Bull Exp Biol Med ; 158(6): 756-61, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25894772

RESUMO

Threefold administration of 3-hydroxypyridine derivatives emoxipine and mexidol in optimal doses corresponding to the therapeutic dose range for humans produced an anxiolytic effect and stimulated risk behavior in the elevated plus maze test in rats. These effects were most pronounced after injection of 3-hydroxypyridine derivative emoxipine. Combination of 3-hydroxypyridine cation and succinate anion in the mexidol structure led to attenuation of the anxiolytic effect and less pronounced stimulation of the risk behavior. By the anxiolytic effect and induction of risk behavior, emoxipine and mexidol were close to the reference substance amitriptyline. Reamberin, a succinic acid derivative, had no pronounced tranquilizing properties, but risk behavior induction was similar to that produced by mexidol. In contrast to other test agents, the reference substance α-lipoic acid produced anxiogenic effects and suppressed risk behavior. The obtained results suggest that Russian-made 3-hydroxypyridine derivatives emoxipine and mexidol are promising preparations for the treatment of anxiety disorders.


Assuntos
Ansiolíticos/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Ácido Succínico/química , Ácido Succínico/uso terapêutico , Animais , Ansiedade/tratamento farmacológico , Feminino , Masculino , Meglumina/análogos & derivados , Meglumina/uso terapêutico , Picolinas/uso terapêutico , Ratos , Assunção de Riscos , Succinatos/uso terapêutico
20.
Klin Khir ; (8): 62-4, 2014 Aug.
Artigo em Ucraniano | MEDLINE | ID: mdl-25417293

RESUMO

On clinical base of cathedra of the disasters medicine, military medicine, anesthesiology and reanimatology in 2010 - 2013 yrs 62 patients were treated for neurotrophic disorders, in 12 of them the method was applied, elaborated in the clinic. For neurotrophic ulcers in 5 patients autodermoplasty was performed, using splitted cutaneous flap, in 1 for the wound defect on a forearm--plasty, using rotational cutaneo-adipose flap, based on axial blood supply. In 44 patients after a spinal cord trauma a neurotrophic defects degree III - IV have formed. The kind of operative intervention was selected depending on size of the defect, the wound depth and functional peculiarities of the injured area. Introduction of a new method of treatment of neurotrophic ulcers of the lower extremities, using preparation of hyaluronic acid with sodium succinate, expands the perspectives of treatment in patients, suffering defects of cover tissues. Differentiated approach to choice of the wound closure method, caused by damage of central and peripheral neural system, have permitted to achieve positive results in 98.1% of patients.


Assuntos
Traumatismos dos Nervos Periféricos/complicações , Procedimentos de Cirurgia Plástica/métodos , Úlcera por Pressão/cirurgia , Traumatismos da Medula Espinal/complicações , Retalhos Cirúrgicos , Combinação de Medicamentos , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/uso terapêutico , Úlcera por Pressão/tratamento farmacológico , Úlcera por Pressão/etiologia , Ácido Succínico/administração & dosagem , Ácido Succínico/uso terapêutico , Resultado do Tratamento , Cicatrização/efeitos dos fármacos
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