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1.
Neurol Sci ; 45(7): 3347-3358, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38393441

RESUMO

There is wide variation in the time from the onset to secondary progressive multiple sclerosis (MS) and some controversy regarding the clinical characteristics of the courses (phenotypes) of MS. The present study aimed to characterize demographic and clinical factors that potentially influence long-term disability progression in the cohort of Latvian MS patients. A descriptive longitudinal incidence study was conducted using a cohort of 288 MS patients beginning in 2011 (disease duration from 1 to 51 years). Socio-demographic and clinical information from the first visit to 15/20 years was analysed in groups stratified by gender and visits at five-time points (the first visit; after a year or 2; after 5 ± 1 year; after 10 ± 2 years; after 15-20 years). Our study was dominated by patients from urban areas and non-smokers. The female/male ratio was 2.4:1; the distribution of clinical courses at the first visit was consistent with most European studies. The most common symptom at presentation in our study was optic manifestations, followed by sensory disturbances and motor deficits. In the Latvian study, gender was not a significant influencing factor on the rate of disease progression; however, patient age was statistically significantly associated with EDSS (Expanded Disability Status Scale) value at the first visit. Early clinical features of MS are important in predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Latvian patients are similar to other regions of the world.


Assuntos
Avaliação da Deficiência , Progressão da Doença , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Estudos de Coortes , População do Leste Europeu , Letônia/epidemiologia , Estudos Longitudinais , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/epidemiologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Crônica Progressiva/epidemiologia
2.
Int J Mol Sci ; 25(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339221

RESUMO

Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the immune system by binding to the nuclear vitamin D receptor (VDR). VDR gene genetic variations are affecting serum vitamin D levels with a possible role in the BA risk. The current study aimed to examine the complex interaction of various factors (genetic background, serum vitamin D levels, and geographic location) to identify differences in the influence of these factors on the susceptibility to asthma between populations at different latitudes. Focusing on Eastern European cohorts from Latvia and Lithuania and comparing them with published data on East Asian populations, we explore the impact of VDR gene polymorphisms on BA susceptibility. Genotyping four key VDR SNPs and assessing their association with 25-hydroxyvitamin D levels, our study unveils significant associations of the studied loci with the risk of asthma-both risk-reducing and increasing effects, differently distributed between Baltic and East Asian populations. The functional effects of in silico VDR gene genetic variations are also identified and discussed.


Assuntos
Asma , Receptores de Calcitriol , Humanos , Receptores de Calcitriol/genética , Predisposição Genética para Doença , Genótipo , Vitamina D/genética , Polimorfismo de Nucleotídeo Único , Asma/genética , Estudos de Casos e Controles
3.
Mutagenesis ; 36(3): 213-222, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34008029

RESUMO

Chronic hyperglycaemia leads to DNA damage in diabetes and might be associated with nitrosative stress. In this study, we aimed at assessing the level of DNA strand breaks in leukocytes, serum nitrite and nitrate in patients with type 1 diabetes and healthy controls and associations of these parameters with diabetes-related outcomes in a prospective study. The level of DNA damage was determined in 71 patients with type 1 diabetes and 57 healthy controls by comet assay and scored with arbitrary units (AU). The chemiluminescence method was used to measure nitrite and nitrate. Clinical information and data on consumption of alcohol, physical activity and smoking were collected. Progression of complications in patients with diabetes was assessed after a follow-up time of 4-5 years. We observed a higher level of DNA damage in leukocytes of patients with type 1 diabetes compared with healthy subjects [type 1 diabetes AU 50 (36-74.5); control AU 30 (24.1-43), P < 0.001]. According to regression, type 1 diabetes leads to a 2-fold increase in DNA damage. In the group of type 1 diabetes, DNA damage correlated positively with total cholesterol (R = 0.262, P = 0.028) and negatively with serum glucose level (R = -0.284; P = 0.018) and serum nitrite (R = -0.335; P = 0.008). DNA damage was not significantly associated with HbA1c, diabetes duration, complications and lifestyle factors. However, DNA damage > 57 AU was associated with statistically significantly lower serum nitrite and 1.52 higher risk of progression of complications of diabetes over the follow-up period. The latter result was not statistically significant due to insufficient study power [relative risk 1.52 (95% confidence interval = 0.68, 3.42, P = 0.31)]. Our results confirm that type 1 diabetes is associated with a higher level of DNA strand breaks in leukocytes when compared with the reference group and demonstrate the negative association between DNA damage and serum nitrite concentration.


Assuntos
Diabetes Mellitus Tipo 1/genética , Leucócitos/patologia , Nitritos/sangue , Adulto , Ensaio Cometa , Dano ao DNA , Complicações do Diabetes/sangue , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Masculino , Estudos Prospectivos
4.
Metab Brain Dis ; 36(7): 1935-1941, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34417942

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease with various factors affecting its etiology. Overproduction of nitric oxide and subsequent lesions of biopolymers are some of the possible causes of the disease. This study aimed to measure the most relevant nitrosative and oxidative stress biomarkers and the level of modified DNA bases in patients with MS. Each parameter was assayed in 25 patients with MS and 25 healthy controls. This study involved detecting blood plasma and serum nitric oxide metabolites by chemiluminescence detector Sievers NOA-280i, malondialdehyde (MDA) measurements with thiobarbituric acid reactive substance (TBARS) assay, detection of oxidized purines and pyrimidines with the enzyme-modified comet assay. Statistical analysis of the results was performed by one-way analysis of variance (ANOVA) and unpaired t test for the comparison of less than three data sets. DNA single-strand breaks, levels of modified purines and pyrimidines, as well as nitrite and nitrate levels in plasma and serum samples, were significantly higher in patients with MS than in healthy controls. On the contrary, MDA levels appeared to be lower in patients with MS.


Assuntos
Esclerose Múltipla , Doenças Neurodegenerativas , Ensaio Cometa , DNA , Dano ao DNA , Humanos , Estresse Nitrosativo , Estresse Oxidativo
5.
Medicina (Kaunas) ; 56(4)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244438

RESUMO

Background and objectives: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, leading to demyelination of neurons and potentially debilitating physical and mental symptoms. The disease is more prevalent in women than in men. The major histocompatibility complex (MHC) region has been identified as a major genetic determinant for autoimmune diseases, and its role in some neurological disorders including MS was evaluated. An intergenic single-nucleotide polymorphism (SNP), rs9275596, located between the HLA-DQB1 and HLA-DQA2 genes, is in significant association with various autoimmune diseases according to genome-wide association studies (GWASs). A cumulative effect of this SNP with other polymorphisms from this region was revealed. The aim of the study was to verify the data on rs9275596 association in multiple sclerosis in a case/control study of the Latvian population and to evaluate eventual functional significance of allele substitutions. Materials and Methods: rs9275596 (chr6:32713854; GRCh38.p12) was genotyped in 273 MS patients and 208 controls on main and sex-specific associations. Eventual functional significance of allele substitutions was evaluated in silico using publicly available tools. Results: The rs9275596 rare alleles were identified as a disease susceptibility factor in association with the MS main group and in affected females (p < 0.001 and p < 0.01, respectively). Risk factor genotypes with rare alleles included were associated with the MS common cohort (p < 0.002) and female cohort (odds ratio, OR = 2.24) and were identified as disease susceptible in males (OR = 2.41). It was shown that structural changes of rs9275596 affect the secondary structure of DNA. Functional significance of allele substitutions was evaluated on the eventual sequence affinity to transcription factors (TFs) and splicing signals similarity. A possible impact of the particular polymorphisms on the transcription and splicing efficiency is discussed. Conclusions: Our results suggest susceptibility of rs9275596 to multiple sclerosis in Latvians.


Assuntos
Cadeias beta de HLA-DQ/análise , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Cadeias beta de HLA-DQ/sangue , Humanos , Letônia/epidemiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/fisiopatologia , Polimorfismo de Nucleotídeo Único/fisiologia
6.
Mol Genet Genomics ; 291(2): 891-903, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26661414

RESUMO

The ubiquitin-proteasome system (UPS), a key player of proteostasis network in the body, was implicated in type 1 diabetes mellitus (T1DM) pathogenesis. Polymorphisms in genes encoding proteasome subunits may potentially affect system efficiency. However, data in this field are still limited. To fulfil this gap, single nucleotide polymorphisms in the PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genes were genotyped on susceptibility to T1DM in Latvians. The rs11543947 was found to be neutral and other loci manifested disease susceptibility, with rs1048990 and rs2348071 being the most significantly associated (P < 0.001; OR 2.042 [1.376-3.032] and OR 2.096 [1.415-3.107], respectively). Risk effect was associated with female phenotype for rs2277460 and family history for rs2277460, rs2295826 and rs2295827. Five-locus genotypes being at risk simultaneously at any two or more loci showed strong (P < 0.0001) T1DM association. The T1DM protective effects (P < 0.001) were shown for five-locus genotype and haplotype homozygous on common alleles and composed of common alleles, respectively. Using SNPexp data set, correlations have been revealed between the rs1048990, rs2295826, rs2295827 and rs2348071 T1DM risk genotypes and expression levels of 14 genes related to the UPS and 42 T1DM-susceptible genes encoding proteins involved in innate and adaptive immunity, antiviral response, insulin signalling, glucose-energy metabolism and other pathways implicated in T1DM pathogenesis. Genotype-phenotype and genotype-genotype clusterings support genotyping results. Our results provide evidence on new T1DM-susceptible loci in the PSMA3, PSMA6 and PSMC6 proteasome genes and give a new insight into the T1DM pathogenesis.


Assuntos
Diabetes Mellitus Tipo 1/genética , Estudos de Associação Genética , Complexo de Endopeptidases do Proteassoma/genética , ATPases Associadas a Diversas Atividades Celulares , Adulto , Alelos , Diabetes Mellitus Tipo 1/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Projeto HapMap , Haplótipos , Humanos , Insulina/genética , Insulina/metabolismo , Letônia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Ubiquitina/genética
7.
Cell Biochem Funct ; 34(1): 3-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26634809

RESUMO

Impaired degradation of proteins by the ubiquitin-proteasome system (UPS) is observed in numerous pathologies including diabetes mellitus (DM) and its complications. Dysregulation of proteasomal degradation might be because of altered expression of genes and proteins involved in the UPS. The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A novel group of 1,4-dihydropyridine (1,4-DHP) derivatives lacking Ca2+-antagonists activities, but capable to produce antidiabetic, antioxidant and DNA repair enhancing effects, were tested for ability to modify Psma6 mRNA expression levels in rat kidneys and blood in healthy animals and in rats with streptozotocin (STZ) induced DM. Psma6 gene was chosen for the study, as polymorphisms of its human analogue are associated with DM and cardiovascular diseases. 1,4-DHP derivatives (metcarbatone, etcarbatone, glutapyrone, J-9-125 and AV-153-Na) were administered per os for three days (0.05 mg/kg and/or 0.5 mg/kg). Psma6 gene expression levels were evaluated by quantitative PCR. Psma6 expression was higher in kidneys compared to blood. Induction of diabetes caused increase of Psma6 expression in kidneys, although it was not changed in blood. Several 1,4-DHP derivatives increased expression of the gene both in kidneys and blood of control and model animals, but greater impact was observed in kidneys. The observed effect might reflect coupling of antioxidant and proteolysis-promoting activities of the compounds.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Di-Hidropiridinas/administração & dosagem , Rim/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Animais , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Rim/efeitos dos fármacos , Masculino , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Regulação para Cima/efeitos dos fármacos
8.
Cell Biochem Funct ; 33(6): 367-74, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26347179

RESUMO

In diabetes mellitus (DM), both hyperglycaemia and hyperlipidaemia can initiate accumulation of fat in the liver, which might be further mediated by inducible nitric oxide synthase. We have studied changes in GLUT1, nitric oxide (NO(·)) concentration and liver damage in two rat DM models. STZ model was induced by strepozotocin 50 mg/kg. HS model was induced by high-fat diet and 30 mg/kg streptozotocin. GLUT1 expression was studied by means of real-time RT-PCR and immunohistochemistry. Production of NO(·) was monitored by means of erythrocyte sedimentation rate spectroscopy of Fe-DETC-NO complex. Liver damage was assessed using histological activity index (HAI). NO(·) concentration was increased in the liver of STZ rats, but it did not change in HS rats (control 36.8 ± 10.3; STZ 142.1 ± 31.1; HS 35.4 ± 9.8 ng/g). Liver HAI was higher in STZ group, 8.6 ± 0.17 versus HS 4.7 ± 0.31, p < 0.05. GLUT1 protein expression was elevated only in STZ group, 16 ± 3 cells/mm(2) versus Control 5 ± 2 cells/mm(2), p = 0.007. Hyperglycaemia sooner causes severe liver damage in rat models of DM, compared with hyperlipidaemia, and is associated with increased NO(·) production. GLUT1 transporter expression might be involved in toxic effects of glucose in the liver. We have obtained novel data about association of GLUT1 expression and NO(·) metabolism in the pathogenesis of liver injury in DM. Increased GLUT1 expression was observed together with overproduction of NO(·) and pronounced liver injury in severely hyperglycaemic rats. On the contrary, moderately hyperglycaemic hyperlipidaemic rats developed only moderate liver steatosis and no increase in GLUT1 and NO(·). GLUT1 overexpression might be implicated in the toxic effects of glucose in the liver. Glycotoxicity is associated with oxidative stress and NO(·) hyperproduction. GLUT1 and NO(·) metabolism might become novel therapeutic targets in liver steatosis.


Assuntos
Diabetes Mellitus Experimental/complicações , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportador de Glucose Tipo 1/metabolismo , Fígado/patologia , Óxido Nítrico/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Transportador de Glucose Tipo 1/toxicidade , Hiperglicemia/metabolismo , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Estreptozocina
9.
Toxins (Basel) ; 16(3)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38535786

RESUMO

Among the various natural compounds used in alternative and Oriental medicine, toxins isolated from different organisms have had their application for many years, and Apis mellifera venom has been studied the most extensively. Numerous studies dealing with the positive assets of bee venom (BV) indicated its beneficial properties. The usage of bee products to prevent the occurrence of diseases and for their treatment is often referred to as apitherapy and is based mainly on the experience of the traditional system of medical practice in diverse ethnic communities. Today, a large number of studies are focused on the antitumor effects of BV, which are mainly attributed to its basic polypeptide melittin (MEL). Previous studies have indicated that BV and its major constituent MEL cause a strong toxic effect on different cancer cells, such as liver, lung, bladder, kidney, prostate, breast, and leukemia cells, while a less pronounced effect was observed in normal non-target cells. Their proposed mechanisms of action, such as the effect on proliferation and growth inhibition, cell cycle alterations, and induction of cell death through several cancer cell death mechanisms, are associated with the activation of phospholipase A2 (PLA2), caspases, and matrix metalloproteinases that destroy cancer cells. Numerous cellular effects of BV and MEL need to be elucidated on the molecular level, while the key issue has to do with the trigger of the apoptotic cascade. Apoptosis could be either a consequence of the plasmatic membrane fenestration or the result of the direct interaction of the BV components with pro-apoptotic and anti-apoptotic factors. The interaction of BV peptides and enzymes with the plasma membrane is a crucial step in the whole process. However, before its possible application as a remedy, it is crucial to identify the correct route of exposure and dosage of BV and MEL for potential therapeutic use as well as potential side effects on normal cells and tissues to avoid any possible adverse event.


Assuntos
Venenos de Abelha , Masculino , Animais , Abelhas , Meliteno , Membrana Celular , Apoptose , Morte Celular
10.
Medicina (Kaunas) ; 49(12): 505-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24858989

RESUMO

The review summarizes literature data on the positive results of association studies between the length of microsatellite repeats and predisposition to pathologies. Actually, the data can be classified according to the localization of the microsatellite: in the gene promoter, in the part of exon 1 coding the signal sequence, in gene introns, in the coding areas of genes, and in 3'-untranslated regions. The functional significance of microsatellite length changes can be evaluated in many cases. The authors came up to the conclusion that further studies on microsatellite associations with diseases remain prospective as they reflect changes in the gene functional activity.


Assuntos
Predisposição Genética para Doença/genética , Repetições de Microssatélites/genética , Regiões 3' não Traduzidas/genética , Éxons/genética , Marcadores Genéticos/genética , Humanos , Íntrons/genética , Regiões Promotoras Genéticas
11.
Toxins (Basel) ; 15(2)2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36828477

RESUMO

Envenomation by animal venoms remains a serious medical and social problem, especially in tropical countries. On the other hand, animal venoms are widely used as a source of biologically active compounds for the development of novel drugs. Numerous derivatives of animal venoms are already used in clinical practice. When analysing the mechanisms of action of animal venoms, attention is usually focused on the main target of the venom's enzymes and peptides such as neurotoxic, cytotoxic or haemorrhagic effects. In the present review, we would like to draw attention to the "hidden" effects of animal venoms and their derivatives in regard to DNA damage and/or protection against DNA damage. Alkaloids and terpenoids isolated from sponges such as avarol, ingenamine G or variolin B manifest the capability to bind DNA in vitro and produce DNA breaks. Trabectidin, isolated from a sea squirt, also binds and damages DNA. A similar action is possible for peptides isolated from bee and wasp venoms such as mastoparan, melectin and melittin. However, DNA lesions produced by the crude venoms of jellyfish, scorpions, spiders and snakes arise as a consequence of cell membrane damage and the subsequent oxidative stress, whereas certain animal venoms or their components produce a genoprotective effect. Current research data point to the possibility of using animal venoms and their components in the development of various potential therapeutic agents; however, before their possible clinical use the route of injection, molecular target, mechanism of action, exact dosage, possible side effects and other fundamental parameters should be further investigated.


Assuntos
Antineoplásicos , Meliteno , Animais , Abelhas , Dano ao DNA
12.
Arh Hig Rada Toksikol ; 74(1): 1-7, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37014687

RESUMO

This review summarises current knowledge about the genotoxic and genoprotective effects of 1,4-dihydropyridines (DHP) with the main focus on the water-soluble 1,4-DHPs. Most of these water-soluble compounds manifest very low calcium channel blocking activity, which is considered "unusual" for 1,4-DHPs. Glutapyrone, diludine, and AV-153 decrease spontaneous mutagenesis and frequency of mutations induced by chemical mutagens. AV-153, glutapyrone, and carbatones protect DNA against the damage produced by hydrogen peroxide, radiation, and peroxynitrite. The ability of these molecules to bind to the DNA may not be the only mechanism of DNA protection, as other mechanisms such as radical scavenging or binding to other genotoxic compounds may take place and enhance DNA repair. These uncertainties and reports of high 1,4-DHP concentrations damaging the DNA call for further in vitro and in vivo preclinical research, pharmacokinetic in particular, as it can help pinpoint the exact mechanism(s) of the genotoxic and/or genoprotective action of 1,4-DHPs.


Assuntos
Bloqueadores dos Canais de Cálcio , Dano ao DNA , Bloqueadores dos Canais de Cálcio/farmacologia , Reparo do DNA
13.
Medicina (Kaunas) ; 48(10): 532-43, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23324250

RESUMO

BACKGROUND AND OBJECTIVE: Glucose transport via GLUT1 protein could be one of additional mechanisms of the antidiabetic action of sulfonylureas. Here, the GLUT1 gene and the protein expression was studied in rats in the course of severe and mild streptozotocin-induced diabetes mellitus and under glibenclamide treatment. MATERIAL AND METHODS: Severe and mild diabetes mellitus was induced using different streptozotocin doses and standard or high fat chow. Rats were treated with glibenclamide (2 mg/kg daily, per os for 6 weeks). The therapeutic effect of glibenclamide was monitored by measuring several metabolic parameters. The GLUT1 mRNA and the protein expression in the kidneys, heart, and liver was studied by means of real-time RT-PCR and immunohistochemistry. RESULTS: The glibenclamide treatment decreased the blood glucose concentration and increased the insulin level in both models of severe and mild diabetes mellitus. Severe diabetes mellitus provoked an increase in both GLUT1 gene and protein expression in the kidneys and the heart, which was nearly normalized by glibenclamide. In the kidneys of mildly diabetic rats, an increase in the GLUT1 gene expression was neither confirmed on the protein level nor influenced by the glibenclamide treatment. In the liver of severely diabetic rats, the heart and the liver of mildly diabetic rats, the GLUT1 gene and the protein expression was changed independently of each other, which might be explained by abortive transcription, and pre- and posttranslational modifications of gene expression. CONCLUSIONS: The GLUT1 expression was found to be affected by the glucose and insulin levels and can be modulated by glibenclamide in severely and mildly diabetic rats. Glibenclamide can prevent the liver damage caused by severe hyperglycemia.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Transportador de Glucose Tipo 1/biossíntese , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Compostos de Sulfonilureia/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Insulina/metabolismo , Secreção de Insulina , Fígado/patologia , Masculino , Biossíntese de Proteínas/efeitos dos fármacos , Ratos , Ratos Wistar
14.
PeerJ ; 10: e13715, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35873915

RESUMO

Diabetic retinopathy (DR) is the most common complication of diabetes, being the most prevalent reason for blindness among the working-age population in the developed world. Despite constant improvement of understanding of the pathogenesis of DR, identification of novel biomarkers of DR is needed for improvement of patient risk stratification and development of novel prevention and therapeutic approaches. The ubiquitin-proteasome system (UPS) is the primary protein quality control system responsible for recognizing and degrading of damaged proteins. This review aims to summarize literature data on modifications of UPS in diabetes and DR. First, we briefly review the structure and functions of UPS in physiological conditions. We then describe how UPS is involved in the development and progression of diabetes and touch upon the association of UPS genetic factors with diabetes and its complications. Further, we focused on the effect of diabetes-induced hyperglycemia, oxidative stress and hypoxia on UPS functioning, with examples of studies on DR. In other sections, we discussed the association of several other mechanisms of DR (endoplasmic reticulum stress, neurodegeneration etc) with UPS modifications. Finally, UPS-affecting drugs and remedies are reviewed. This review highlights UPS as a promising target for the development of therapies for DR prevention and treatment and identifies gaps in existing knowledge and possible future study directions.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Animais , Humanos , Citoplasma/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/etiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo
15.
J Clin Med ; 11(10)2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35628895

RESUMO

The aim of the study was to compare telomere lengths and circulating proteasome concentrations in patients with different stages of diabetic retinopathy and type 1 diabetes in Latvia and Lithuania. Methods. Patients with no diabetic retinopathy and with non-proliferative diabetic retinopathy were included in the NDR/NPDR group (n = 187). Patients with proliferative diabetic retinopathy and status post laser-photocoagulation were included int the PDR/LPC group (n = 119). Telomeres were evaluated by real-time quantitative polymerase chain reaction. Proteasome concentration was measured by ELISA. Results. Telomeres were longer in PDR/LPC (ΔCT 0.21 (0.12−0.28)) vs. NDR/NPDR (ΔCT 0.18 (0.1−0.28)), p = 0.036. In NDR/NPDR, telomeres were correlated negatively with age (R = −0.17, p = 0.019), BMI (R = −0.21, p = 0.004), waist/hip ratio (R = −0.21, p = 0.005), total cholesterol (R = −0.18, p = 0.021), and low-density cholesterol (R = −0.20, p = 0.010), and positively with estimated glomerular filtration rate (eGFR) (R = 0.28, p < 0.001). None of the above correlations were observed in PRD/LPC. Proteasome concentrations were lower in PDR/LPC (130 (90−210) ng/mL) vs. NDR/NPDR (150 (100−240) ng/mL), p = 0.024. This correlated negatively with eGFR (R = −0.17, p = 0.025) in the NDR/NPDR group and positively with age (R = 0.23, p = 0.014) and systolic blood pressure (R = 0.20, p = 0.032) in the PRD/LPC group. Telomere lengths did not correlate with proteasome concentrations. Conclusion. Longer telomeres and lower circulating proteasome concentrations are observed in patients with type 1 diabetes and advanced diabetic retinopathy.

16.
Cell Biochem Funct ; 29(1): 55-63, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21264891

RESUMO

Anti-ischaemic drug mildronate suppresses fatty acid metabolism and increases glucose utilization in myocardium. It was proposed that it could produce a favourable effect on metabolic parameters and glucose transport in diabetic animals. Rats with streptozotocin diabetes mellitus were treated with mildronate (100 mg/kg daily, per os, 6 weeks). Therapeutic effect of mildronate was monitored by measuring animal weight, concentrations of blood glucose, insulin, blood triglycerides, free fatty acids, blood ketone bodies and cholesterol, glycated haemoglobin per cent (HbA1c%) and glucose tolerance. GLUT1 mRNA and protein expression in kidneys, heart, liver and muscles were studied by means of real time RT-PCR and immunohistochemistry correspondingly. In the streptozotocin + mildronate group, mildronate treatment caused a significant decrease in mean blood glucose, cholesterol, free fatty acid and HbA1c concentrations and improved glucose tolerance. Induction of streptozotocin diabetes mellitus provoked increase of both GLUT1 gene and protein expression in kidneys, heart and muscle, mildronate treatment produced normalization of the GLUT1 expression levels. In the liver a similar effect was observed for GLUT1 protein expression, while GLUT1 gene expression was increased by mildronate. Mildronate produces therapeutic effect in streptozotocin diabetes model. Mildronate normalizes the GLUT1 expression up-regulated by streptozotocin diabetes mellitus in kidneys, heart, muscle and liver. Copyright © 2011 John Wiley & Sons, Ltd.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Transportador de Glucose Tipo 1/metabolismo , Hipoglicemiantes/farmacologia , Metilidrazinas/farmacologia , RNA Mensageiro/metabolismo , Estreptozocina/farmacologia , Animais , Glicemia/efeitos dos fármacos , Tamanho Corporal/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 1/sangue , Transportador de Glucose Tipo 1/efeitos dos fármacos , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Insulina/sangue , Insulina/metabolismo , Metilidrazinas/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina/efeitos adversos , Triglicerídeos/sangue , Triglicerídeos/metabolismo
17.
Eur J Histochem ; 65(2)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33942598

RESUMO

The review summarizes literature data on the role of DNA breaks and DNA repair in differentiation of pluripotent stem cells (PSC) and connective cell lineages. PSC, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), are rapidly dividing cells with highly active DNA damage response (DDR) mechanisms to ensure the stability and integrity of the DNA. In PSCs, the most common DDR mechanism is error-free homologous recombination (HR) that is primarily active during S phase of the cell cycle, whereas in quiescent, slow-dividing or non-dividing tissue progenitors and terminally differentiated cells, error-prone non-homologous end joining (NHEJ) mechanism of the double-strand break (DSB) repair is dominating.  Thus, it seems that reprogramming and differentiation induce DNA strand breaks in stem cells which itself may trigger the differentiation process. Somatic cell reprogramming to iPSCs is preceded by a transient increase of the DSBs induced presumably by the caspase-dependent DNase or reactive oxygen species (ROS). In general, pluripotent stem cells possess stronger DNA repair systems compared to the differentiated cells. Nonetheless, during a prolonged cell culture propagation, DNA breaks can accumulate due to the DNA polymerase stalling. Consequently, the DNA damage might trigger the differentiation of stem cells or a replicative senescence of somatic cells. Differentiation process per se is often accompanied by a decrease of the DNA repair capacity. Thus, the differentiation might be triggered by DNA breaks, alternatively the breaks can be a consequence of the decay in the DNA repair capacity of differentiated cells.


Assuntos
Diferenciação Celular/genética , Células do Tecido Conjuntivo/metabolismo , Quebras de DNA , Reparo do DNA/fisiologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Animais , Condrogênese/genética , Humanos , Osteogênese/genética
18.
Chem Biol Interact ; 348: 109638, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508711

RESUMO

The DNA-binding activities of compounds used as remedies can display DNA-protection, but also damaging effects in biological systems. The current review compiles literature data on DNA-binding activities of drugs widely used as remedies with different therapeutic indications. The compounds are classified according their mechanism of action: enzyme inhibitors, ion channel inhibitors, inhibitors of viral RNA replication and HIV protease and receptor agonists. DNA binding was reported for such widely used drugs as paracetamol, aspirin, metformin, statins and many others. The capability of the drug to bind DNA is sometimes coupled to genotoxic effects, but in some cases - to genome protection. Data on atoms and chemical groups involved in the drug-DNA interactions are also presented. In many cases the same atoms are involved in both interactions of the compounds with proteins and DNA.


Assuntos
DNA/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Canais Iônicos/antagonistas & inibidores , Animais , Humanos
19.
Arh Hig Rada Toksikol ; 72(3): 148-156, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34187104

RESUMO

The ubiquitin-proteasome system modifies different cellular and protein functions. Its dysregulation may lead to disrupted proteostasis associated with multiple pathologies and aging. Pharmacological regulation of proteasome functions is already an important part of the treatment of several diseases. 1,4-dihydropyridine (1,4-DHP) derivatives possess different pharmacological activities, including antiaging and neuroprotective. The aim of this study was to investigate the effects of several 1,4-DHP derivatives on mRNA expression levels of proteasomal genes Psma3, Psmb5, and Psmc6 in several organs of rats. Rats were treated with metcarbatone, etcarbatone, glutapyrone, styrylcarbatone, AV-153-Na, or AV-153-Ca per os for three days. mRNA expression levels were determined with real-time polymerase chain reaction (PCR). For AV-153-Na and AV-153-Ca, we also determined the expression of the Psma6 gene. In the kidney, metcarbatone, etcarbatone, styrylcarbatone, and AV-153-Na increased the expression of all analysed genes. Glutapyrone increased the expression of Psmb5 and Psmc6 but did not affect the expression of Psma3. In the blood, glutapyrone increased Psmb5 expression. In the liver, AV-153-Na increased the expression of Psma6 and Psmc6 but lowered the expression of Psmb5, while AV-153-Ca only increased Psma6 expression. The ability of 1,4-DHP derivatives to increase the expression of proteasome subunit genes might hold a therapeutic potential in conditions associated with impaired proteasomal functions, but further research is needed.


Assuntos
Rim , Complexo de Endopeptidases do Proteassoma , Animais , Di-Hidropiridinas , Complexo de Endopeptidases do Proteassoma/genética , RNA Mensageiro/genética , Ratos
20.
Exp Ther Med ; 21(5): 478, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33767773

RESUMO

Several polymorphisms in genes related to the ubiquitin-proteasome system exhibit an association with pathogenesis and prognosis of various human autoimmune diseases. Our previous study reported the association between multiple sclerosis (MS) and the PSMA3-rs2348071 polymorphism in the Latvian population. The current study aimed to evaluate the PSMA6 and PSMC6 genetic variations, their interaction between each other and with the rs2348071, on the susceptibility to MS risk and response to therapy in the Latvian population. PSMA6-rs2277460, -rs1048990 and PSMC6-rs2295826, -rs2295827 were genotyped in the MS case/control study and analysed in terms of genotype-protein correlation network. The possible association with the disease and alleles, single- and multi-locus genotypes and haplotypes of the studied loci was assessed. Response to therapy was evaluated in terms of 'no evidence of disease activity'. To the best of our knowledge, the present study was the first to report that single- and multi-loci variations in the PSMA6, PSMC6 and PSMA3 proteasome genes may have contributed to the risk of MS in the Latvian population. The results of the current study suggested a potential for the PSMA6-rs1048990 to be an independent marker for the prognosis of interferon-ß therapy response. The genotype-phenotype network presented in the current study provided a new insight into the pathogenesis of MS and perspectives for future pharmaceutical interventions.

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