One of the most common chronic liver disorders, affecting mainly people in Western countries, is nonalcoholic fatty liver disease (NAFLD). Unfortunately, its pathophysiological mechanism is not fully ...understood, and no dedicated treatment is available. Simple steatosis can lead to nonalcoholic steatohepatitis and even to fibrosis, cancer, and cirrhosis of the liver. NAFLD very often occurs in parallel with type 2 diabetes mellitus and in obese people. Furthermore, it is much more likely to develop in patients with metabolic syndrome (MS), whose criteria include abdominal obesity, elevated blood triacylglycerol level, reduced high-density lipoprotein cholesterol level, increased blood pressure, and high fasting glucose. An important phenomenon in MS is also insulin resistance (IR), which is very common in NAFLD. Liver IR and NAFLD development are linked through an interaction between the accumulation of free fatty acids, hepatic inflammation, and increased oxidative stress. The liver is particularly exposed to elevated levels of reactive oxygen species due to a large number of mitochondria in hepatocytes. In these organelles, the main DNA repair pathway is base excision repair (BER). The present article will illustrate how impairment of BER may be related to the development of NAFLD.
Nanoparticles have many applications both in industry and medicine. Depending upon their physical and chemical properties, they can be used as carriers of therapeutic molecules or as therapeutics. ...Nanoparticles are made of synthetic or natural polymers, lipids or metals. Their use allows for faster transport to the place of action, thus prolonging its presence in the body and limiting side effects. In addition, the use of such a drug delivery system protects the drug from rapid disintegration and elimination from the body. In recent years, the use of proteins and peptides as therapeutic molecules has grown significantly. Unfortunately, proteins are subject to enzymatic digestion and can cause unwanted immune response beyond therapeutic action. The use of drug carriers can minimize undesirable side effects and reduce the dose of medication needed to achieve the therapeutic effect. The current study presents the use of several selected drug delivery systems for the delivery of proteins, peptides and other therapeutic molecules.
In 2018, 550,000 people were diagnosed with bladder cancer (BC), of which nearly 200,000 people died. Moreover, men are 4 times more likely than women to be diagnosed with BC. The risk factors ...include exposure to environmental and occupational chemicals, especially tobacco smoke, benzidine and genetic factors. Despite numerous studies, the molecular basis of BC development remains unclear. A growing body of evidence suggests that inflammation, oxidant-antioxidant imbalance and angiogenesis disorders may play a significant role in the development and progression of bladder cancer. The patients with bladder cancer were characterised by an increased level of reactive oxygen species (ROS), the products of lipid peroxidation, proinflammatory cytokines and proangiogenic factors as compared to controls. Furthermore, it was shown that polymorphisms localised in genes associated with these pathways may modulate the risk of BC. Interestingly, ROS overproduction may induce the production of proinflammatory cytokines, which finally activated angiogenesis. Moreover, the available literature shows that both inflammation and oxidative stress may lead to activation of angiogenesis and tumour progression in BC patients.
Urolithiasis is one of the most common urological diseases worldwide with an unclear aetiology. However, a growing body of evidence suggests the potential role of molecular disturbances of the ...inflammation as well as oxidative and nitrative stresses, in the pathogenesis of urolithiasis. Therefore, we aimed to detect the potential association between six selected single-nucleotide polymorphisms (SNPs) and the development of nephrolithiasis. Moreover, we verified the association of urolithiasis development and mRNA expression of
IL-6
,
IL-8
,
SOD2
, and
NOS2
in peripheral blood mononuclear cells (PBMCs). Total genomic DNA and mRNA were isolated from the peripheral blood of 112 patients with urolithiasis and 114 healthy subjects. Using Taq-Man® probes, we genotyped the following SNPs: rs1800797 and rs2069845 in
IL-6
, rs2227307 in
IL-8
, rs4880 in
SOD2
, rs2297518 and rs2779249 in
NOS2
. In turn, the evaluation of mRNA expression was performed using real-time PCR and 2
-ΔCt
methods. We found that the C/T genotype of the c.47 T>C–
SOD2
SNP increased the frequency of urolithiasis occurrence whereas the T/T homozygote of the same polymorphism decreased the risk of urolithiasis development in the Polish population. Moreover, our study confirmed that patients with urolithiasis were characterised by decreased
IL-6
,
IL-8
, and
SOD2
mRNA expression levels compared to the controls. In conclusion, our results suggest that polymorphic variants and changes in mRNA expression of
IL-6
,
IL8
,
SOD2
, and
NOS2
may be involved in the pathophysiology of urolithiasis.
Sirtuin1 is an epigenetic enzyme involved in histone and nonhistone protein deacetylation. It acts primarily as a metabolic sensor, which responses to changing energy status by deacetylating crucial ...transcription factors and cofactors. In this way, Sirtuin1 regulates mitochondrial function and biogenesis, oxidative stress, inflammation, apoptosis and cellular senescence. Disturbance of all of these phenomena promotes the pathogenesis of diabetic complications. These disorders are inseparably connected with chronic hyperglycemia, which possesses a strong epigenetic determinant.
To summarize the contemporary knowledge regarding the role of Sirtuin1 in the development, progression and therapy of diabetic complications.
We extensively searched literature describing the importance of Sirtuin1 in pathophysiology and treatment of all kinds of diabetic complications till September 2017. We focused on the examples of synthetic and natural compounds-mediated Sirtuin1 upregulation along with Sirtuin1-associated epigenetics.
Reduction of Sirtuin1 is implicated in endothelial dysfunction and metabolic memory, underlying the development of micro- and macrovascular complications. Declined Sirtuin1 also participates in diabetic testicular and erectile dysfunction. Sirtuin1 is elevated by naturally occurring anti-oxidant and anti-inflammatory compounds such as resveratrol, trans-δ-viniferin, vitamin D and more. Similarly, Sirtuin1 level increases after treatment with standard antihyperglycemic (metformin, exenatide, liraglutide), antihypertensive (sartans), lipid-lowering (fibrates, statins) and anticoagulant (fidarestat) drugs. Regarding epigenetics, a number of miRNAs trigger Sirtuin1 decrease, which further contributes to histone acetylation of Sirtuin1-regulated and relevant for diabetes genes.
Evidence strongly suggest that Sirtuin1 upregulation may serve as a potent therapeutic approach against development and progression of diabetic complications.
Abstract Background MMPs play a role in modulating inflammation and their impact in many inflammatory diseases has been investigated. The aim of the study was to demonstrate the relationship between ...selected polymorphisms for MMP-2 (C-735T), MMP-7 (A-181G), MMP-9 (T-1702A, C1562T) and TIMP-2 (G-418C) and depression, as well as between the importance of distribution of genotypes and alleles for the examined polymorphisms and the risk of depression occurrence. Methods The examined population comprised 203 individuals suffering from depression and 99 individuals who formed a control group. Designations were carried out for MMP-2 (C-735T), MMP-7 (A-181G), MMP-9 (T-1702A, C1562T) and TIMP-2 (G-418C). The distribution of haplotypes of the MMP-9 T-1702A and MMP-9 C1562T was specified for MMP-9 (T-1702A, C1562T). Results In rDD group and in the control group the presence of the T-1702A polymorphism for MMP-9 increases the risk of rDD development for the T/T genotype and T allele ( OR =2.191). The A/A genotype (OR=0.120) and A allele (OR=0.442) reduce the risk of disease occurrence in the examined polymorphisms for MMP-2, MMP-7 and MMP-9. The C/C genotype and C allele of the C1562T MMP-9 polymorphism increase the risk of middle-age depression, while the T allele makes this risk smaller. The incidence of rDD was greater for the C/T C-735T /MMP-2/ genotype and G/G A-181G /MMP-7/ genotype. A similarly high risk of incidence was confirmed for the C/T – T/T genotypes of the MMP-2 C-735T and MMP-9 T-1702A polymorphisms. A higher risk of incidence (OR=9.376) was confirmed in the case of a set of T/T-G/C genotypes of the MMP-9 T-1702A and TIMP-2 G-418C polymorphisms. For the gene-gene interactions presented above, a statistically significant difference was found between the examined group and the control group. Limitations A small group of examined patients and the need for conducting the study in other populations in order to determine the impact of the stratification factor. Conclusions 1.The evaluated polymorphisms in MMP genes have significant importance for the development of depression; they also have an impact on depression onset. 2. Further studies focused on changes of MMPs in the development of rDD are required.
Chloroxylenol (PCMX) is applied as a preservative and disinfectant in personal care products, currently recommended for use to inactivate the SARS-CoV-2 virus. Its intensive application leads to the ...release of PCMX into the environment, which can have a harmful impact on aquatic and soil biotas. The aim of this study was to assess the mechanism of chloroxylenol biodegradation by the fungal strains
IM 1785/21GP and
IM 373, and investigate the ecotoxicity of emerging by-products. The residues of PCMX and formed metabolites were analysed using GC-MS. The elimination of PCMX in the cultures of tested microorganisms was above 70%. Five fungal by-products were detected for the first time. Identified intermediates were performed by dechlorination, hydroxylation, and oxidation reactions catalysed by cytochrome P450 enzymes and laccase. A real-time quantitative PCR analysis confirmed an increase in CYP450 genes expression in
cells. In the case of
, spectrophotometric measurement of the oxidation of 2,20-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) showed a significant rise in laccase activity during PCMX elimination. Furthermore, with the use of bioindicators from different ecosystems (Daphtoxkit F and Phytotoxkit), it was revealed that the biodegradation process of PCMX had a detoxifying nature.
Rationale
N−3 polyunsaturated fatty acids (n−3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis.
Objectives
A ...randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n−3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n−3 PUFA clinical effect and changes in peripheral BDNF levels.
Methods
Seventy-one patients aged 16–35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains.
Results
A significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen’s
d
= 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson’s
r
= − 0.195;
p
= 0.018).
Conclusions
The efficacy of a six-month intervention with n−3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.
Bladder cancer (BC) is the 10th most common form of cancer globally, but its complete aetiology is still unknown. Nevertheless, there is evidence that chronic inflammation plays a role in the ...development and progression of BC. Therefore, the presented study aimed to detect a potential association between selected single nucleotide polymorphisms (SNPs)-rs1800797 and rs2069845 in
and rs2227307 in
-and BC development, as well as to identify the impact of BC on the level of expression and methylation of
and
promoters in PBMCs with the use of the TaqMan SNP genotyping assay, TaqMan gene expression assay, and methylation-sensitive high-resolution melting techniques. We did not find any association between the genotypes and combined genotypes of all studied polymorphisms and the occurrence of BC. However, we found that BC patients were characterised by decreased
and
mRNA expression levels compared to the controls. Additionally, the methylation status of the
promoter was higher in controls than in BC patients. Our findings suggest that inflammation may be involved in the development and progression of BC.
The tumor resistance of glioblastoma cells in vivo is thought to be enhanced by their heterogeneity and plasticity, which are extremely difficult to curb in vitro. The external microenvironment ...shapes the molecular profile of tumor culture models, thus influencing potential therapy response. Our study examines the expression profile of selected lncRNAs involved in tumor resistance network in three different glioblastoma-derived models commonly utilized for testing drug response in vitro. Differential expression analysis revealed significant divergence in lncRNA profile between parental tumors and tumor-derived cell cultures in vitro, including the following particles: MALAT1, CASC2, H19, TUSC7, XIST, RP11-838N2.4, DLX6-AS1, GLIDR, MIR210HG, SOX2-OT. The examined lncRNAs influence the phenomenon of tumor resistance via their downstream target genes through a variety of processes: multi-drug resistance, epithelial–mesenchymal transition, autophagy, cell proliferation and viability, and DNA repair. A comparison of in vivo and in vitro expression identified differences in the levels of potential lncRNA targets, with the highest discrepancies detected for the
MDR1
,
LRP1
,
BCRP
and
MRP1
genes. Co-expression analyses confirmed the following interrelations: MALAT1–TYMS, MALAT1–MRP5, H19–ZEB1, CASC2–VIM, CASC2–N-CAD; they additionally suggest the possibility of MALAT1–BCRP, MALAT1–mTOR and TUSC7–PTEN interconnections in glioblastoma. Although our results clearly demonstrate that the artificial ex vivo microenvironment changes the profile of lncRNAs related to tumor resistance, it is difficult to anticipate the final phenotypic effect, since this phenomenon is a complex one that involves a network of molecular interactions underlying a variety of cellular processes.
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