RESUMO
A clinical observation of the use of Cytoflavin according to a two-stage scheme (10.0 ml intravenously drip per 200 ml of 0.9% sodium chloride solution for 10 days, followed by a transition to a tablet form of 2 tablets 2 times/day for 25 days) in a patient with postcovid syndrome with pronounced vegetative and neurocognitive disorders. The effectiveness of therapy was confirmed by an improvement in heart rate variability and a decrease in the severity of depression, anxiety (on the HADS scale) and the level of autonomic dysfunction (on the COMPASS-31 scale). The significant changes in levels of fatigue (on a scale MFI) is not marked. The obtained results can serve as a basis for further research.
Assuntos
Inosina Difosfato , Niacinamida , Humanos , Niacinamida/uso terapêutico , Mononucleotídeo de Flavina/uso terapêutico , Combinação de Medicamentos , Inosina Difosfato/uso terapêutico , Succinatos/uso terapêuticoRESUMO
OBJECTIVE: To evaluate the effectiveness of the Cytoflavin in patients with dyscirculatory encephalopathy (DE) who had a new coronavirus infection. MATERIAL AND METHODS: 82 patients were examined: 16 (19.5%) men and 66 (80.5%) women aged 58 to 80 years, mean age 69±6 years and 70±6 years, respectively. All patients had moderate vascular cognitive impairment (less than 26 points according to the MoCA test), a history of COVID-19 in the period from 3 to 12 months before the start of the study. Patients before COVID-19 were registered with a neurologist with chronic cerebrovascular diseases with non-demented cognitive impairment of vascular origin. Patients of the main group (MG) received the Cytoflavin from the 1st to the 25th day of observation, inclusive, 2 tablets 2 times a day against the background of standard basic therapy. Patients in the comparison group received only standard basic therapy. RESULTS: It was found that during therapy with Cytoflavin, patients noted a positive trend in the form of a decrease in the symptoms of cognitive impairment, improved orientation and working memory, concentration of attention and counting. Also, patients in MG noted a decrease in fatigue and depressive disorders, an increase in motivation and a positive attitude, the emergence of interest in life, an improvement in the emotional background of mood, an increase in physical activity and working capacity. Comparing the mechanisms of development of vascular dysfunction, a pathogenetic commonality between DE and the development of consequences in the form of cognitive impairment caused by COVID-19 was noted. CONCLUSION: Cytoflavin therapy at a dosage of 2 tablets 2 times a day for 25 days can be recommended as part of complex therapy for patients with DE and a COVID-19.
Assuntos
Encefalopatias , COVID-19 , Inosina Difosfato , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Inosina Difosfato/uso terapêutico , Niacinamida/uso terapêuticoRESUMO
OBJECTIVE: The purpose of the present double-blind, placebo-controlled, randomized clinical trial was to evaluate the efficacy and safety of Cytoflavin in patients with diabetic polyneuropathy (DPN). MATERIAL AND METHODS: Investigational therapy was administered in two steps: intravenous infusions of experimental drug/placebo for 10 days followed by oral administration for 75 days. In 10 clinical centers, 216 patients aged 45-74 years with a diagnosis of type 2 diabetes mellitus, symptomatic distal sensorimotor DPN, confirmed no earlier than 1 year before screening, on stable therapy (no change of drugs and doses) by oral hypoglycemic drugs, intermediate-acting, long-acting or extra-long-acting insulin, and/or GLP-1 receptor agonists. RESULTS: By the end of treatment, the change of the Total Symptom Score (TSS) in the experimental group was -2.65 points, in the placebo group -1.73 points (p<0.001). Improvement of symptoms in the experimental group was achieved regardless of the degree of compensation for type 2 diabetes (both in those with Hb1Ac <8.0% and in those with Hb1Ac ≥8.0%), but demonstrated better results in patients with less severe baseline symptoms (TSS <7.5). Improvement in the components of the TSS scale «paresthesia¼ and «numbness¼ occurred as early as on day 11 of therapy; by the end of treatment, a significant decrease in the «burning¼ component was also demonstrated. The experimental drug had a positive safety profile. CONCLUSION: Cytoflavin, intravenous solution and enteric-coated tablets (SPTF Polysan Ltd.) is indicated for the symptomatic treatment of DPN.
Assuntos
Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Inosina Difosfato , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Inosina Difosfato/efeitos adversos , Niacinamida/efeitos adversosRESUMO
The knowledge of accurate geometrical parameters from X-ray diffraction studies in the solid state of metal nucleotide is very important for understanding the relationship between structures and properties, including biochemical processes and even enzyme-metal-substrate interactions. The research is also very necessary to precisely and controllably design the functional materials. Here, seven types of coordination polymers of inosine 5'-diphosphate nucleotide (IDP) with transition metals, {[Zn(HIDP)(azpy)(H2O)2]·4H2O}n (1), {[Cd2(IDP)2(bpda)2]·[Cd(H2O)6]·11H2O}n (2), {[Cd3(IDP)2(4,4'-bipy)2(H2O)3]·6H2O}n (3), {[Cd2(IDP)2(bpe)2(H2O)2]·(H2bpe)·26H2O}n (4), {[Cu3(IDP)2(azpy)2(H2O)5]·5H2O}n (5), {[Cu3(IDP)2(bpe)2(H2O)5]·9H2O}n (6), and {[Co(HIDP)(azpy)(H2O)2]·7H2O}n (7) [4,4'-bipy = 4,4'-bipyridine, azpy = 4,4'-azopyridine, bpe = 1,2-bis(4-pyridyl)ethene, and bpda = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene], were designed, synthesized, and firmly characterized using single-crystal X-ray diffraction. The coordination patterns of the diphosphate group of IDP in these complexes were studied by crystallographic analysis, namely, open, close, and open-close hybrid types. We have investigated the diverse coordination patterns of the diphosphate group and its spatial relationship relative to the pentose ring on the basis of two conformational parameters, the pseudorotation phase angle and the degree of puckering. Crystallographic studies clearly reveal the correlation between the backbone torsion angle (ω' and φ) of the sugar-diphosphate and the conformational preference of the pentose ring, i.e., the signs of the backbone torsion angles ω' and φ are both plus (+) or minus (-), the conformation of the pentose ring is envelope form (E), while when one of the two signs is plus (+) and the other is minus (-), the pentose ring is in the twist form (T). This is the first time elucidation of the coordination pattern of diphosphate relative to the conformation of the pentose ring in nucleotide metal complexes, which are different from the other inorganic or organic diphosphate compounds. The chirality of these coordination polymers was examined by combining solid-state circular dichroism spectroscopy measurements with the explanation of their crystal structures. The results presented in this paper are very important for understanding their nucleotide coordination chemistry, their supramolecular chemistry, and even their biochemistry.
Assuntos
Complexos de Coordenação , Inosina Difosfato , Difosfatos , Cádmio , Nucleotídeos , PolímerosRESUMO
OBJECTIVE: Determination of the total antioxidant activity of blood serum (AOA) of patients with chronic cerebral ischemia (CCI) I-II st. against the background of treatment with Cytoflavin or ethylmethylhydroxypyridine succinate (EMGPS) and evaluation of the effect of drugs on the state of cognitive functions and emotional sphere of patients. MATERIAL AND METHODS: The main group consisted of 12 women with CCI I-II st., treated on an outpatient basis with Cytoflavin 1 tablet 2 times/day as part of complex therapy for 1 month; 12 patients with CCI I-II st., treated as part of complex therapy with EMGPS 125 mg 2 times/day for 1 month we made a comparison group. The groups are comparable in age, gender, the nature of risk factors, the severity of neurological manifestations, and the nature of basic therapy. The state of AOA, the severity and nature of cognitive and emotional disorders were assessed. RESULTS: It was found that the inclusion of Cytoflavin or EMGPS in complex therapy equally increased the AOA of patients. The decrease in the severity of neurological deficit during treatment consisted in improving spatio-temporal gnosis by improving the relationships in the cortex and synchronizing the activity of its different departments with the rate of nervous activity and neurophysiological characteristics different for each drug. The use of both drugs led to a decrease in the selection reaction time and the number of errors in recognizing the angular velocity of movement. Cytoflavin increased the selectivity of perception and attention in patients, while EMGPS did not affect this indicator. CONCLUSION: The use of Cytoflavin and EMGPS leads to an increase in AOA, has various effects on the cognitive functions of patients with CCI.
Assuntos
Isquemia Encefálica , Inosina Difosfato , Humanos , Feminino , Antioxidantes/uso terapêutico , Inosina Difosfato/uso terapêutico , Niacinamida/uso terapêuticoRESUMO
OBJECTIVE: To investigate the structure of postcovid syndrome, age and gender characteristics of its course, and to assess the effect of Cytoflavin on the clinical course of neurological disorders in patients who have undergone COVID-19. MATERIAL AND METHODS: The study included 100 patients, the average age was 40.4±11.7 years, there were statistically more men than women. The duration of the transferred SARS-CoV-2 days is from 30 to 90 days from the date of recovery). By random sampling, the patients were divided into two groups, the main group, received Cytoflavin tablets, a course of 25 days, 2 tablets 2 times a day. Comparison group - other drugs (vitamins, nootropic drugs). All patients were examined on the day of treatment and 25-30 days after the end of therapy. The status was assessed using Asthenia Assessment Scale (MFI-20), Brief Mental Status Assessment Scale (MMSE), Quality-of-Life Questionnaire (EQ-5D), General Health Assessment Scale, and Pittsburgh Sleep Quality Index (PSQI). The analysis of laboratory parameters was carried out retrospectively. RESULTS AND CONCLUSION: Postcovid syndrome was more common in men, among comorbid conditions arterial hypertension and atherosclerosis prevailed, neurocognitive and autonomic disorders predominated. Appointment of Cytoflavin made it possible to achieve a pronounced anti-asthenic effect with the correction of cognitive impairments, which was reflected in a significantly more significant positive dynamics of indicators of all scales. An additional effect of Cytoflavin was revealed - a decrease in the severity of thrombocytopenia. During the observation period, no patient had any serious adverse events or side effects associated with taking the drug. Prescription of the drug does not require age-related dose adjustment and is well combined with basic therapy for concomitant pathology.
Assuntos
COVID-19 , Adulto , Combinação de Medicamentos , Feminino , Mononucleotídeo de Flavina , Humanos , Inosina Difosfato , Masculino , Pessoa de Meia-Idade , Niacinamida , Estudos Prospectivos , Estudos Retrospectivos , SARS-CoV-2 , Qualidade do Sono , Succinatos , Resultado do TratamentoRESUMO
Continuous improvement of protocols for the treatment of various ailments, in particular, osteochondrosis, is one of the important tasks of providing medical care to elderly patients. Supplementation of treatment with Cytoflavin and biofeed-back therapy seems to be a promising solution, however, it is necessary to develop an algorithm to predict it effectiveness in patients taking into account their initial clinical and psychophysiological status. As a result of the treatment, predictors of the effectiveness of the use of Cytoflavin and biofeed-back therapy have been identified and an algorithm for their administration has been developed.
Assuntos
Inosina Difosfato , Osteocondrose , Idoso , Algoritmos , Combinação de Medicamentos , Mononucleotídeo de Flavina , Humanos , Niacinamida , Succinatos , Resultado do TratamentoRESUMO
One of the ways to improve the condition of the elderly body is the method of auto-training with biofeedback, as a means of correcting deviations in the functioning of the regulatory apparatus, as well as improving antioxidant protection and eliminating the effects of oxidative stress using Cytoflavin therapy. These methods seem to be a simple and effective means of correcting negative changes in the FS of elderly hockey players after a training cycle and ensuring the possibility of a more complete recovery of their body. The difference in the points of application made it possible to combine the intake of Cytoflavin and biofeedback training into a single complex correctional and restorative technique. Purpose of the research: to consider the organizational and methodological aspects of introducing a comprehensive methodology for correcting the functional state of elderly hockey players into the system of support of their training process. Based on the results of the study, we have obtained convincing data on the positive effect of the inclusion of Cytoflavin and biofeedback training in the system of medical support for the training process of elderly hockey players. The organizational and methodological aspects of introducing a comprehensive methodology for correcting the functional state of older hockey players into the system of support for their training process considered in this article make it possible to solve a number of problems facing medical workers regarding continuous monitoring of the functional state of older hockey players, proactive diagnosis of their negative deviations, as well as a system of reabilitation.
Assuntos
Hóquei , Idoso , Antioxidantes , Combinação de Medicamentos , Mononucleotídeo de Flavina , Humanos , Inosina Difosfato , Niacinamida , SuccinatosRESUMO
For assaying serum creatinine, the enzymatic method is regarded as accurate. However, a reliable measurement of low levels is problematic. We have developed a new method that utilizes an enzymatic cycling reaction involving creatine kinase (CK) in the presence of excess ATP and IDP and implicated the application to a serum creatinine assay by incorporating with creatininase. Here, we evaluated applying the CK cycling method to a serum creatinine assay. In this study, we focused on assessing whether an accurate measurement could be achieved, especially in the reference interval and the lower concentration range. The effective sensitivity of the assay using 30 U/mL CK was approximately 4-fold greater than that of a commercial reagent. Under these conditions, 0.19 mg/dL of creatinine was accurately detected. The correlation coefficient of the comparison study with an existing commercial reagent was 0.995. Moreover, the effect of the increased signal intensity on accuracy and precision was assured.
Assuntos
Amidoidrolases/química , Bioensaio , Creatina Quinase/química , Creatinina/sangue , NADP/química , Trifosfato de Adenosina/química , Glucose/química , Glucosefosfato Desidrogenase/química , Humanos , Indicadores e Reagentes/química , Inosina Difosfato/química , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , SoluçõesRESUMO
OBJECTIVE: To study therapy, including a sequential course of the drug Cytoflavin, on the dynamics of neurological and general status in patients with new coronavirus infection COVID-19. MATERIAL AND METHODS: 47 patients with a new coronavirus infection COVID-19, admitted to the hospital and having a state of moderate severity, according to the criteria of the Interim Guidelines of the Ministry of Health of the Russia for the prevention, diagnosis and treatment of a new coronavirus infection (COVID-19, version 9 of 10.26.2020). Clinical and neurological research, laboratory and instrumental examination methods were used before and after the course of therapy. RESULTS: When a sequential Cytoflavin regimen is used in patients with COVID-19 infection, along with standard therapy, a significant improvement in neurological and general status is observed, as well as a significant positive dynamics in the results of laboratory and instrumental research methods (markers of a systemic inflammatory response, hemostasis and oxygenation disorders), which indicates on the influence of the significant effect of Cytoflavin on the processes of inflammation and hypercoagulability in COVID-19 infection. CONCLUSION: The use of the drug Cytoflavin in the complex therapy of patients with COVID-19 infection is pathogenetically justified and expedient. The data obtained make it possible to recommend the inclusion of Cytoflavin in the treatment protocols for patients with COVID-19 coronavirus infection to optimize therapy and improve the course and outcome of the disease, as well as a longer use of Cytoflavin and repeated courses of its use in patients with COVID-19 infection.
Assuntos
COVID-19 , Inosina Difosfato , Combinação de Medicamentos , Mononucleotídeo de Flavina/uso terapêutico , Humanos , Inosina Difosfato/uso terapêutico , Niacinamida , SARS-CoV-2 , Succinatos/uso terapêutico , Resultado do TratamentoRESUMO
Examination of the patterns of free-radical processes (FRP) and changes of the early screening markers to predict the course of hemorrhagic stroke (HS) and applied pathophysiologically based therapy can be of great practical importance. This study aimed to determine early changes in the parameters of oxidative stress and routine biochemistry blood tests in patients with HS and to assess their relationship with clinical outcome. The effects of early applied cytoflavin were also investigated. The prospective study included 151 patients with HS. Forty-eight percent of patients in the standard conservative therapy were given cytoflavin antioxidant energy therapy from the first day of hospitalization. The neurological status, neuroimaging, biochemical blood tests and FRP were assessed on days 1, 5, 10, and 20 of hospitalization. In patients with HS, an imbalance of all stages of FRP was detected proportionately to the severity of HS. The malondialdehyde concentration above 5.3 µmol/L, the number of leukocytes above 15 800, glucose above 11.9 mmol/L, lactate dehydrogenase above 574 IU/L, and lactate above 2.5 mmol/L, detected on the first day, predetermined a high risk of death. Additional cytoflavin treatment allowed stabilizing the clinical laboratory picture of HS, improved the treatment results, and reduced hospital mortality rate.
Assuntos
Antioxidantes/administração & dosagem , Mononucleotídeo de Flavina/administração & dosagem , Acidente Vascular Cerebral Hemorrágico/mortalidade , Inosina Difosfato/administração & dosagem , Niacinamida/administração & dosagem , Succinatos/administração & dosagem , Idoso , Animais , Biomarcadores/sangue , Glicemia , Encéfalo/diagnóstico por imagem , Combinação de Medicamentos , Feminino , Acidente Vascular Cerebral Hemorrágico/sangue , Acidente Vascular Cerebral Hemorrágico/diagnóstico , Acidente Vascular Cerebral Hemorrágico/tratamento farmacológico , Mortalidade Hospitalar , Humanos , L-Lactato Desidrogenase/sangue , Ácido Láctico/sangue , Imageamento por Ressonância Magnética , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Prognóstico , Estudos Prospectivos , Medição de Risco/métodos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
We evaluated the protective effect of ademetionine, cytoflavin, and dihydroquercetin on activity of serum enzymes in rats treated with high doses of sodium valproate for 28 days. Ademetionine and cytoflavin produced the greatest protective effect, the effect of dihydroquercetin was less pronounced. In rats treated with ademetionine, AST activity decreased as soon as on day 7 and remained at this level until the end of the experiment; ALT, alkaline phosphatase, and γ-glutamyl transferase activities decreased on days 21 and 28 of the study. Cytoflavin produced similar effects, the effect of dihydroquercetin was observed on days 21 and 28 for AST, ALT, alkaline phosphatase and on day 28 for γ-glutamyl transferase. These results substantiate the use of hepatoprotective drugs in case of long-term treatment with anticonvulsants in patients with epilepsy.
Assuntos
Anticonvulsivantes/farmacologia , Eritrócitos/efeitos dos fármacos , Mononucleotídeo de Flavina/farmacologia , Inosina Difosfato/farmacologia , Niacinamida/farmacologia , Quercetina/análogos & derivados , S-Adenosilmetionina/farmacologia , Succinatos/farmacologia , Ácido Valproico/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Anticonvulsivantes/efeitos adversos , Combinação de Medicamentos , Epilepsia/tratamento farmacológico , Fígado/efeitos dos fármacos , Masculino , Quercetina/farmacologia , Ratos , Fatores de Tempo , Ácido Valproico/efeitos adversos , gama-Glutamiltransferase/metabolismoRESUMO
OBJECTIVE: To assess an effect of cytoflavin on the results of rehabilitation treatment and the increase in exercise tolerance in patients with stroke complicated by post-intensive care syndrome (PICS). MATERIAL AND METHODS: The data of 53 patients who underwent neurorehabilitation in the ICU after ischemic stroke were analyzed. Depending on the treatment regimen, the patients were divided into two groups. Group 1 (main, n=36) received cytoflavin (iv drip in a volume of 10 ml of a solution for injections per 200 ml of a 0.9% solution of sodium chloride) for 10 days in addition to the complex of neurorehabilitation measures. Group 2 (control, n=17) included patients, who had only a standard set of neurorehabilitation measures for 10 days. The efficacy of the therapy was evaluated using indirect calorimetry, and the oxygen and energy load price index was calculated. To assess the tolerability of rehabilitation methods, a verticalization test was used. Treatment tolerance was assessed by the incidence of adverse reactions in each group. RESULTS AND CONCLUSION: The components of the energytropic effect of cytoflavin can have a positive modulating effect, increasing the tolerance of rehabilitation measures for the treatment of PICS in patients with ischemic stroke. Further research is required.
Assuntos
Isquemia Encefálica , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Cuidados Críticos , Combinação de Medicamentos , Mononucleotídeo de Flavina/uso terapêutico , Humanos , Inosina Difosfato , Niacinamida , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Succinatos/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To substantiate the advisability of using cytoflavin to correct postoperative cognitive dysfunction (POCD) in patients undergoing video laparoscopic cholecystectomy (VLCE) under conditions of inhalation anesthesia with sevoflurane. MATERIAL AND METHODS: The data of two representative groups of patients (n=60) who underwent video-laparoscopic cholecystectomy under the conditions of inhalation anesthesia with sevoflurane were analyzed. At the stages of the perioperative period, in order to monitor the state of higher mental functions, neuropsychological testing was performed: anxiety and depression scales (HADS), the Montreal scale of cognitive dysfunction (MoCA), and frontal dysfunction batteries (FAB). Patients of the first group (n=19) were not corrected for POKD. For the correction of cognitive impairment, patients of the second group (n=41) were treated with Cytoflavin according to the 20 ml regimen per 250 ml of 0.9% sodium chloride solution intravenously once before the operation, then within 4 days of the postoperative period. RESULTS: Neuropsychological testing in group I patients revealed the development of moderate POCD. The inclusion of Cytoflavin in the treatment regimen in the II group of patients contributed to an improvement in the state of HMF, accompanied by a decrease in the level of anxiety and depression. CONCLUSION: The inclusion of Cytoflavin in treatment regimens helps prevent the development of POKD and is accompanied by an improvement in the state of higher mental functions, which is manifested by a decrease in the level of anxiety and depression, favorably affecting the emotional background of patients.
Assuntos
Anestésicos Inalatórios/efeitos adversos , Colecistectomia Laparoscópica , Transtornos Cognitivos/terapia , Mononucleotídeo de Flavina/administração & dosagem , Inosina Difosfato/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Niacinamida/administração & dosagem , Sevoflurano/efeitos adversos , Succinatos/administração & dosagem , Anestesia por Inalação/efeitos adversos , Anestesia por Inalação/métodos , Colecistectomia Laparoscópica/efeitos adversos , Colecistectomia Laparoscópica/métodos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Combinação de Medicamentos , Humanos , Cirurgia VídeoassistidaRESUMO
OBJECTIVE: To study the efficacy and safety of the complex metabolic neuroprotective medicine cytoflavin in tablet form in patients with vertigo and dizziness in a distant period of mild traumatic brain injury. MATERIAL AND METHODS: Forty patients, aged 20-55 years, with a mild traumatic brain injury were studied for 3 months to 1 year. Cytoflavin was used as monotherapy in a dose of 2 tablets 2 times a day for 25 days. Otoneurological and stabilometric examinations were performed before and after treatment. The Dizziness Handicap Inventory, a visual-analogous scale and HADS were administered. RESULTS AND CONCLUSION: Cytoflavin decreases the severity of vertigo and dizziness, improves stabilometric indicators and reduces emotional disorders in patients with vertigo in the distant period of mild traumatic brain injury. No significant adverse reactions are observed.
Assuntos
Concussão Encefálica , Inosina Difosfato , Adulto , Tontura , Combinação de Medicamentos , Mononucleotídeo de Flavina , Humanos , Pessoa de Meia-Idade , Niacinamida , Succinatos , Vertigem , Adulto JovemRESUMO
BACKGROUND: The transcription-inhibitory G-Quadruplex(Pu27-GQ) at c-MYC promoter is challenging to target due to structural heterogeneity. Nucleoside diphosphate kinase (NM23-H2) specifically binds and unfolds Pu27-GQ to increase c-MYC transcription. Here, we used Inosine 5'-diphosphate (IDP) to disrupt NM23-H2-Pu27-GQ interactions and arrest c-MYC transcription without compromising NM23-H2-mediated kinase properties. METHODS: Site-directed mutagenesis,31P-NMR and STD-NMR studies delineate the epitope of NM23-H2-IDP complex and characterize specific amino acids in NM23-H2 involved in Pu27-GQ and IDP interactions. Immunoprecipitations and phosphohistidine-immunoblots reveal how IDP blocks NM23-H2-Pu27 association to downregulate c-MYC transcription in MDAMB-231 cells exempting NM23-H2-mediated kinase properties. RESULTS: NMR studies show that IDP binds to the Guanosine diphosphate-binding pocket of NM23-H2 (KD = 5.0 ± 0.276 µM). Arg88-driven hydrogen bonds to the terminal phosphate of IDP restricts P-O-P bond-rotation increasing its pKa (∆pKa = 0.85 ± 0.0025).9-inosinyl moiety of IDP is stacked over Phe60 phenyl ring driving trans-conformation of inosine and axial geometry of pyrophosphates. Chromatin immunoprecipitations revealed that these interactions rescue NM23-H2-driven Pu27-GQ unfolding, which triggers Nucleolin recruitment and lowers Sp1 occupancy at c-MYC promoter stabilizing Pu27-GQ. This silences c-MYC transcription that reduces c-MYC-Sp1 association amplifying Sp1 recruitment across P21 promoter stimulating P21 transcription and G2/M arrest. CONCLUSIONS: IDP synergizes the effects of Pu27-GQ-interacting compounds to abrogate c-MYC transcription and induce apoptosis in MDAMB-231 cells by disrupting NM23-H2-Pu27-GQ interactions without affecting NM23-H2-mediated kinase properties. GENERAL SIGNIFICANCE: Our study provides a pragmatic approach for developing NM23-H2-targeting regulators to rescue NM23-H2 binding at structurally ambiguous Pu27-GQ that synergizes the anti-tumorigenic effects of GQ-based therapeutics with minimized off-target effects.
Assuntos
Quadruplex G , Inosina Difosfato/metabolismo , Núcleosídeo-Difosfato Quinase/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Pontos de Checagem da Fase M do Ciclo Celular , Modelos Moleculares , Núcleosídeo-Difosfato Quinase/química , Regiões Promotoras Genéticas/genética , Conformação Proteica , Transcrição GênicaRESUMO
Currently, the actual problem is the correction of motor, cognitive and psychoemotional disorders in physiological aging, as well as in various pathological processes that accompany aging and accelerate it. In this regard, it became necessary to search for drugs that can restore age-related disorders of the brain. The aim of the study was to evaluate the possibility of Cytoflavin as a pharmacological corrector of age-dependent disorders of the functions of the cerebral cortex during physiological and pathological, accelerated aging. The mouse sensorimotor cortex of the brain was the material for study. The transgenic male mice with HER2/neu overexpression at the age of 2 and 10 months were used as an experimental model, male wild-type FBV/N mice at the age of 2 and 18 months served as a control. We studied locomotor activity, orientational research behavior and the psychoemotional status of animals using the «open field¼ test and the Suok test. It was found that in old FBV/N mice, after the cytoflavin treatment, recovery of locomotor functions and orientational-research behavior is observed. Under conditions of HER2/neu overexpression after the Cytoflavin treatment, an improvement in motor functions occurs. It was also shown that the studied drug has an anxiolytic effect on both wild-type FBV/N mice and transgenic HER2/neu mice during aging. Thus, the positive effect of Cytoflavin on the dynamics of the behavior of experimental mice during physiological and pathological accelerated aging allow to suggest that in the late stages of ontogenesis, Cytoflavin restores the cerebral cortex functions and prevents neurodegeneration.
Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Emoções/efeitos dos fármacos , Mononucleotídeo de Flavina/farmacologia , Inosina Difosfato/farmacologia , Locomoção/efeitos dos fármacos , Niacinamida/farmacologia , Succinatos/farmacologia , Animais , Combinação de Medicamentos , Masculino , CamundongosRESUMO
AIM: To evaluate the efficacy of including cytoflavin in rehabilitation measures in the early recovery period of patients with ischemic stroke. MATERIAL AND METHODS: Results of rehabilitation measures of 100 patients (50 women and 50 men, aged 18 to 85 years) in the early recovery period of ischemic stroke were analyzed. Psychological testing included NIHSS, MMSE, Rankin scale, Rivermead mobility index, exercise tolerance test. Depending on the rehabilitation scheme, patients were divided into the main group (n=50), who received a verticalization course and cytoflavin (intravenously, drip 20.0 ml in 250.0 ml 5% glucose for 14 days). The control group (n=50) included patients who received standard treatment. RESULTS AND CONCLUSION: Inclusion of cytoflavin in the rehabilitation scheme for patients with ischemic stroke increased the effectiveness of treatment, which was manifested by a decrease in the severity of neurological disorders assessed with NIHSS by 17.6% in the main group versus 10.8% in the control group (p<0.05) and recovery of cognitive functions assessed with MMSE by 5.8% versus 1.6%, respectively (p<0.05). In addition, there was a positive dynamics in the restoration of blood pressure (by 37.1% in the main group versus 30.6% in the control group (p<0.05)).
Assuntos
Isquemia Encefálica/terapia , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Cognição/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Mononucleotídeo de Flavina/administração & dosagem , Mononucleotídeo de Flavina/farmacologia , Mononucleotídeo de Flavina/uso terapêutico , Humanos , Inosina Difosfato/administração & dosagem , Inosina Difosfato/farmacologia , Inosina Difosfato/uso terapêutico , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Acidente Vascular Cerebral/metabolismo , Succinatos/administração & dosagem , Succinatos/farmacologia , Succinatos/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
We present a scheme for transferring conformational degrees of freedom from all-atom (AA) simulations of an intrinsically disordered protein (IDP) to coarse-grained (CG) Monte Carlo (MC) simulations using conformational swap moves. AA simulations of a single histatin 5 peptide in water were used to obtain a structural ensemble, which is reweighted in a CGMC simulation in the presence of a negatively charged surface. For efficient sampling, the AA trajectory was condensed using two approaches: RMSD clustering (based on the root-mean-square difference in atom positions) and a "naiÌve" truncation, where only every 100th frame of the trajectory was included in the library. The results show that even libraries with few structures well reproduce the radius of gyration and interaction free energy as functions of the distance from the surface. We further observe that the surface slightly promotes the secondary structure of histatin 5 and more so if using explicit surface charges rather than smeared charges.
Assuntos
Inosina Difosfato/metabolismo , Termodinâmica , Humanos , Método de Monte Carlo , Conformação ProteicaRESUMO
OBJECTIVE: To evaluate the efficacy and safety of Сytoflavin in the treatment of cognitive and emotional disorders in patients with tension headache. MATERIAL AND METHODS: Fifty patients with tension headache, aged from 18 to 50 years, were studied. The following methods and tests were used: neurological examination, NPRS, STAI, CFQ, RAVLT, TOVA, electroencephalography (routine and spectral analysis). The patients were treated with Сytoflavin. RESULTS: After the treatment, clinical improvement was observed in 62.0% of the patients. A significant decrease in trait anxiety and inattention, as well as an improvement of memory performance were observed. A comparative analysis of neurophysiological results before and after the treatment showed a decrease in the manifestations of dysfunction of nonspecific regulation of the brain. CONCLUSION: The results of this study demonstrate the efficacy of Cytoflavin in the treatment of tension headache and associated emotional and cognitive impairments.