Dihydroquercetin and biochaga reduce H2O2 induced DNA damage in peripheral blood mononuclear cells of obese women in vitro-a pilot study.

Systemic oxidative stress stemming from increased free radical production and reduced antioxidant capacity are common characteristics of obese individuals. Using hydrogen peroxide (H2O2) to induce DNA damage in vitro, in peripheral blood mononuclear cells (PBMCs) from obese subjects and controls, the DNA protective ability of dihidroqercetin (DHQ) and biochaga (B) alone or in combination, were evaluated. The effects of DHQ and B were estimated under two experimental conditions: pre-treatment, where cells were pre-incubated with the substances prior to H2O2 exposure; and post-treatment when cells were first exposed to H2 H2O2, and further treated with the compounds. DNA damage was evaluated using the comet assay. The results of pre- and post-treatment showed a significant decrease in DNA damage produced by H2O2 in the obese group. This decrease was not significant in control group probably due to a small number of subjects in this pilot study. More prominent attenuation was noted in the pre-treatment with DHQ (250 µg/mL). Analysis of antioxidant properties revealed that DHQ's remarkable reducing power, 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity, and potent ∙OH scavenging properties may contribute to strong attenuation of H2O2 induced DNA damage. Also, B showed strong reducing power, DPPH, and ∙OH scavenging ability, while reducing power and DPPH scavenger effects were increased in the presence of DHQ. Conclusively, DHQ and B may reduce H2O2-induced DNA damage in PBMCs from obese subjects when challenged in vitro, and could be valuable tools in future research against oxidative damage-related conditions.

Novel insights regarding the role of noncoding RNAs in diabetes.

Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.

MicroRNA networks linked with BRCA1/2, PTEN, and common genes for Alzheimer's disease and breast cancer share highly enriched pathways that may unravel targets for the AD/BC comorbidity treatment.

MicroRNAs (miRNAs) are involved in the regulation of various cellular processes including pathological conditions. MiRNA networks have been extensively researched in age-related degenerative diseases, such as cancer, Alzheimer's disease (AD), and heart failure. Thus, miRNA has been studied from different approaches, in vivo, in vitro, and in silico including miRNA networks. Networks linking diverse biomedical entities unveil information not readily observable by other means. This work focuses on biological networks related to Breast cancer susceptibility 1 (BRCA1) in AD and breast cancer (BC). Using various bioinformatics approaches, we identified subnetworks common to AD and BC that suggest they are linked. According to our results, miR-107 was identified as a potentially good candidate for both AD and BC treatment (targeting BRCA1/2 and PTEN in both diseases), accompanied by miR-146a and miR-17. The analysis also confirmed the involvement of the miR-17-92 cluster, and miR-124-3p, and highlighted the importance of poorly researched miRNAs such as mir-6785 mir-6127, mir-6870, or miR-8485. After filtering the in silico analysis results, we found 49 miRNA molecules that modulate the expression of at least five genes common to both BC and AD. Those 49 miRNAs regulate the expression of 122 genes in AD and 93 genes in BC, from which 26 genes are common genes for AD and BC involved in neuron differentiation and genesis, cell differentiation and migration, regulation of cell cycle, and cancer development. Additionally, the highly enriched pathway was associated with diabetic complications, pointing out possible interplay among molecules underlying BC, AD, and diabetes pathology.

DES-Amyloidoses "Amyloidoses through the looking-glass": A knowledgebase developed for exploring and linking information related to human amyloid-related diseases.

More than 30 types of amyloids are linked to close to 50 diseases in humans, the most prominent being Alzheimer's disease (AD). AD is brain-related local amyloidosis, while another amyloidosis, such as AA amyloidosis, tends to be more systemic. Therefore, we need to know more about the biological entities' influencing these amyloidosis processes. However, there is currently no support system developed specifically to handle this extraordinarily complex and demanding task. To acquire a systematic view of amyloidosis and how this may be relevant to the brain and other organs, we needed a means to explore "amyloid network systems" that may underly processes that leads to an amyloid-related disease. In this regard, we developed the DES-Amyloidoses knowledgebase (KB) to obtain fast and relevant information regarding the biological network related to amyloid proteins/peptides and amyloid-related diseases. This KB contains information obtained through text and data mining of available scientific literature and other public repositories. The information compiled into the DES-Amyloidoses system based on 19 topic-specific dictionaries resulted in 796,409 associations between terms from these dictionaries. Users can explore this information through various options, including enriched concepts, enriched pairs, and semantic similarity. We show the usefulness of the KB using an example focused on inflammasome-amyloid associations. To our knowledge, this is the only KB dedicated to human amyloid-related diseases derived primarily through literature text mining and complemented by data mining that provides a novel way of exploring information relevant to amyloidoses.

Type 2 Diabetes Mellitus and its comorbidity, Alzheimer's disease: Identifying critical microRNA using machine learning.

MicroRNAs (miRNAs) are critical regulators of gene expression in healthy and diseased states, and numerous studies have established their tremendous potential as a tool for improving the diagnosis of Type 2 Diabetes Mellitus (T2D) and its comorbidities. In this regard, we computationally identify novel top-ranked hub miRNAs that might be involved in T2D. We accomplish this via two strategies: 1) by ranking miRNAs based on the number of T2D differentially expressed genes (DEGs) they target, and 2) using only the common DEGs between T2D and its comorbidity, Alzheimer's disease (AD) to predict and rank miRNA. Then classifier models are built using the DEGs targeted by each miRNA as features. Here, we show the T2D DEGs targeted by hsa-mir-1-3p, hsa-mir-16-5p, hsa-mir-124-3p, hsa-mir-34a-5p, hsa-let-7b-5p, hsa-mir-155-5p, hsa-mir-107, hsa-mir-27a-3p, hsa-mir-129-2-3p, and hsa-mir-146a-5p are capable of distinguishing T2D samples from the controls, which serves as a measure of confidence in the miRNAs' potential role in T2D progression. Moreover, for the second strategy, we show other critical miRNAs can be made apparent through the disease's comorbidities, and in this case, overall, the hsa-mir-103a-3p models work well for all the datasets, especially in T2D, while the hsa-mir-124-3p models achieved the best scores for the AD datasets. To the best of our knowledge, this is the first study that used predicted miRNAs to determine the features that can separate the diseased samples (T2D or AD) from the normal ones, instead of using conventional non-biology-based feature selection methods.

Alzheimer's and Consciousness: How Much Subjectivity Is Objective?

Does Alzheimer Disease show a decline in cognitive functions that relate to the awareness of external reality? In this paper, we will propose a perspective that patients with increasing symptoms of AD show a change in the awareness of subjective versus objective representative axis of reality thus consequently move to a more internal like perception of reality. This paradigm shift suggests that new insights into the dynamicity of the conscious representation of reality in the AD brain may give us new clues to the very early signs of memory and self-awareness impairment that originates from, in our view the microtubules. Dialog between Adso and William, in Umberto Eco's The Name of the Rose, Third Day: Vespers. "But how does it happen," I said with admiration, "that you were able to solve the mystery of the library looking at it from the outside, and you were unable to solve it when you were inside?" "Thus, God knows the world, because He conceived it in His mind, as if it was from the outside, before it was created, and we do not know its rule, because we live inside it, having found it already made."

Strawberry (Fragaria ananassa duch.) Alba extract attenuates DNA damage in lymphocytes of patients with Alzheimer's disease.

Increased levels of oxidative stress and oxidative DNA damage are common features in the pathology of Alzheimer's disease (AD) found in neurons and peripheral cells like peripheral blood lymphocytes (PBL). Natural products such as strawberry cultivar Alba are an important source of bioactive nutrients that could help in lowering both the oxidative stress and DNA damage levels. The objective was to estimate the effects of Alba extract on DNA damage in peripheral blood lymphocytes of sporadic AD (aged 60-84 years) patients, and healthy elderly (aged 69-83 years) and young (aged 21-30 years) individuals in in vitro conditions. Comet assay was used as a sensitive technique for the evaluation of PBL DNA damage levels. Reduction of basal DNA damage level in PBL was shown in the young group after the incubation with Alba extract ranging from 25 to 200 µg/ml, with 100 µg/ml being the most effective concentration. Selected Alba extract of 100 µg/ml was further used for PBL treatment of AD and healthy elderly age matched group, displaying potential to significantly attenuate DNA damage levels in both groups (p < .05). Alba extract displayed biological activity against oxidative DNA damage, suggesting that its functional ingredients may have beneficial health effects. PRACTICAL APPLICATIONS: The data obtained in this preliminary study displayed that strawberry Alba extract is efficient against DNA damage induced by endogenous and exogenous oxidative stress in peripheral blood lymphocytes of Alzheimer`s disease in vitro. An active area of future research of Alba cultivar should be to determine the trials in in vivo systems. Our findings also suggest that Alba cultivar's functional ingredients potentially may have beneficial health effects in AD.

DES-ROD: Exploring Literature to Develop New Links between RNA Oxidation and Human Diseases.

Normal cellular physiology and biochemical processes require undamaged RNA molecules. However, RNAs are frequently subjected to oxidative damage. Overproduction of reactive oxygen species (ROS) leads to RNA oxidation and disturbs redox (oxidation-reduction reaction) homeostasis. When oxidation damage affects RNA carrying protein-coding information, this may result in the synthesis of aberrant proteins as well as a lower efficiency of translation. Both of these, as well as imbalanced redox homeostasis, may lead to numerous human diseases. The number of studies on the effects of RNA oxidative damage in mammals is increasing by year due to the understanding that this oxidation fundamentally leads to numerous human diseases. To enable researchers in this field to explore information relevant to RNA oxidation and effects on human diseases, we developed DES-ROD, an online knowledgebase that contains processed information from 298,603 relevant documents that consist of PubMed abstracts and PubMed Central full-text articles. The system utilizes concepts/terms from 38 curated thematic dictionaries mapped to the analyzed documents. Researchers can explore enriched concepts, as well as enriched pairs of putatively associated concepts. In this way, one can explore mutual relationships between any combinations of two concepts from used dictionaries. Dictionaries cover a wide range of biomedical topics, such as human genes and proteins, pathways, Gene Ontology categories, mutations, noncoding RNAs, enzymes, toxins, metabolites, and diseases. This makes insights into different facets of the effects of RNA oxidation and the control of this process possible. The usefulness of the DES-ROD system is demonstrated by case studies on some known information, as well as potentially novel information involving RNA oxidation and diseases. DES-ROD is the first knowledgebase based on text and data mining that focused on the exploration of RNA oxidation and human diseases.

Redox control of vascular biology.

Redox control is lost when the antioxidant defense system cannot remove abnormally high concentrations of signaling molecules, such as reactive oxygen species (ROS). Chronically elevated levels of ROS cause oxidative stress that may eventually lead to cancer and cardiovascular and neurodegenerative diseases. In this review, we focus on redox effects in the vascular system. We pay close attention to the subcompartments of the vascular system (endothelium, smooth muscle cell layer) and give an overview of how redox changes influence those different compartments. We also review the core aspects of redox biology, cardiovascular physiology, and pathophysiology. Moreover, the topic-specific knowledgebase DES-RedoxVasc was used to develop two case studies, one focused on endothelial cells and the other on the vascular smooth muscle cells, as a starting point to possibly extend our knowledge of redox control in vascular biology.

Proton Pump Inhibitors and Radiofrequency Ablation for Treatment of Barrett's Esophagus.

Gastroesophageal Reflux Disease (GERD) is characterized by acid and bile reflux in the distal oesophagus, and this may cause the development of reflux esophagitis and Barrett's oesophagus (BE). The natural histological course of untreated BE is non-dysplastic or benign BE (ND), then lowgrade (LGD) and High-Grade Dysplastic (HGD) BE, with the expected increase in malignancy transfer to oesophagal adenocarcinoma (EAC). The gold standard for BE diagnostics involves high-resolution white-light endoscopy, followed by uniform endoscopy findings description (Prague classification) with biopsy performance according to Seattle protocol. The medical treatment of GERD and BE includes the use of proton pump inhibitors (PPIs) regarding symptoms control. It is noteworthy that long-term use of PPIs increases gastrin level, which can contribute to transfer from BE to EAC, as a result of its effects on the proliferation of BE epithelium. Endoscopy treatment includes a wide range of resection and ablative techniques, such as radio-frequency ablation (RFA), often concomitantly used in everyday endoscopy practice (multimodal therapy). RFA promotes mucosal necrosis of treated oesophagal region via high-frequency energy. Laparoscopic surgery, partial or total fundoplication, is reserved for PPIs and endoscopy indolent patients or in those with progressive disease. This review aims to explain distinct effects of PPIs and RFA modalities, illuminate certain aspects of molecular mechanisms involved, as well as the effects of their concomitant use regarding the treatment of BE and prevention of its transfer to EAC.

Antigenotoxic Effects of Biochaga and Dihydroquercetin (Taxifolin) on H2O2-Induced DNA Damage in Human Whole Blood Cells.

The health benefits of natural products have long been recognized. Consumption of dietary compounds such as supplements provides an alternative source of natural products to those obtained from the diet. There is a growing concern regarding the possible side effects of using different food supplements simultaneously, since their possible interactions are less known. For the first time, we have tested genotoxic and antigenotoxic effects of Biochaga, in combination with dihydroquercetin. No genotoxic effect on whole blood cells was observed within individual treatment of Biochaga (250 µg/mL, 500 µg/mL and 1000 µg/mL) and dihydroquercetin (100 µg/mL, 250 µg/mL and 500 µg/mL), nor in combination. Afterwards, antigenotoxic potency of both supplements against hydrogen peroxide- (H2O2-) induced DNA damage to whole blood cells (WBC) was assessed, using the comet assay. Biochaga and dihydroquercetin displayed a strong potential to attenuate H2O2-induced damage on DNA in cells at all tested concentrations, with a statistical significance (p < 0.05), whereas Biochaga at the dose of 500 µg/mL in combination with dihydroquercetin 500 µg/mL was most prominent. Biochaga in combination with dihydroquercetin is able to protect genomic material from oxidative damage induced by hydrogen peroxide in vitro.

Dry olive leaf extract attenuates DNA damage induced by estradiol and diethylstilbestrol in human peripheral blood cells in vitro.

Phenolic groups of steroidal or nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17ß-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 µM (P < 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P < 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells' antioxidant capacity.

Antigenotoxic and antioxidant potential of medicinal mushrooms (Immune Assist) against DNA damage induced by free radicals-an in vitro study.

Immune Assist (IA) is produced from extract of six species of medical mushrooms: Agaricus blazei - Cordyceps sinensis - Grifola frondosa - Ganoderma lucidum - Coriolus versicolor - Lentinula edodes. The genoprotective potential of IA was evaluated for the first time. Significant antigenotoxic effects were detected in human peripheral blood cells against H2O2 induced DNA damage, in the pretreatment and in the posttreatment. The most efficient concentration of IA in pretreatment was 500 µg/mL, while in posttreatment it was the concentration of 250 µg/mL. Kinetics of attenuation of H2O2 induced DNA damage in posttreatment with the optimal concentration of IA showed significant decrease in the number of damaged cells at all time periods (15-60 min), reaching the greatest reduction after 15 and 45 min. Remarkable ·OH scavenging properties and moderate reducing power, together with the modest DPPH scavenging activity, could be responsible for the great attenuation of DNA damage after 15 min of exposure to IA, while reduction of DNA damage after 45 min could be the result in additional stimulation of the cell's repair machinery. Our results suggest that IA displayed antigenotoxic and antioxidant properties. A broader investigation of its profile in biological systems is needed.

Literature-Based Enrichment Insights into Redox Control of Vascular Biology.

In cellular physiology and signaling, reactive oxygen species (ROS) play one of the most critical roles. ROS overproduction leads to cellular oxidative stress. This may lead to an irrecoverable imbalance of redox (oxidation-reduction reaction) function that deregulates redox homeostasis, which itself could lead to several diseases including neurodegenerative disease, cardiovascular disease, and cancers. In this study, we focus on the redox effects related to vascular systems in mammals. To support research in this domain, we developed an online knowledge base, DES-RedoxVasc, which enables exploration of information contained in the biomedical scientific literature. The DES-RedoxVasc system analyzed 233399 documents consisting of PubMed abstracts and PubMed Central full-text articles related to different aspects of redox biology in vascular systems. It allows researchers to explore enriched concepts from 28 curated thematic dictionaries, as well as literature-derived potential associations of pairs of such enriched concepts, where associations themselves are statistically enriched. For example, the system allows exploration of associations of pathways, diseases, mutations, genes/proteins, miRNAs, long ncRNAs, toxins, drugs, biological processes, molecular functions, etc. that allow for insights about different aspects of redox effects and control of processes related to the vascular system. Moreover, we deliver case studies about some existing or possibly novel knowledge regarding redox of vascular biology demonstrating the usefulness of DES-RedoxVasc. DES-RedoxVasc is the first compiled knowledge base using text mining for the exploration of this topic.

Glutathione "Redox Homeostasis" and Its Relation to Cardiovascular Disease.

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired "redox homeostasis," which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction.

The X Files: "The Mystery of X Chromosome Instability in Alzheimer's Disease".

Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of individuals worldwide and can occur relatively early or later in life. It is well known that genetic components, such as the amyloid precursor protein gene on chromosome 21, are fundamental in early-onset AD (EOAD). To date, however, only the apolipoprotein E4 (ApoE4) gene has been proved to be a genetic risk factor for late-onset AD (LOAD). In recent years, despite the hypothesis that many additional unidentified genes are likely to play a role in AD development, it is surprising that additional gene polymorphisms associated with LOAD have failed to come to light. In this review, we examine the role of X chromosome epigenetics and, based upon GWAS studies, the PCDHX11 gene. Furthermore, we explore other genetic risk factors of AD that involve X-chromosome epigenetics.

Homocysteine and Hyperhomocysteinaemia.

Homocysteine (Hcy) is a thiol group containing the amino acid, which naturally occurs in all humans. Hcy is degraded in the body through two metabolic pathways, while a minor part is excreted through kidneys. The chemical reactions that are necessary for degradation of Hcy require the presence of folic acid, vitamins B6 and B12. Consequently, the level of the total Hcy in the serum is influenced by the presence or absence of these vitamins. An elevated level of the Hcy, hyperhomocysteinemia (HHcy) and homocystinuria is connected with occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer's disease, pregnancy problems, and others. Elevated Hcy levels are connected with various pathologies both in adult and child population. Causes of HHcy include genetic mutations and enzyme deficiencies in 5, 10-methylenetetrahydrofolate reductase (MTHFR) methionine synthase (MS), and cystathionine ß-synthase (CßS). HHcy can be caused by deficiencies in the folate, vitamin B12 and to a lesser extent, deficiency in B6 vitamin what influences methionine metabolism. Additionally, HHcy can be caused by the rich diet and renal impairment. This review presents literature data from recent research related to Hcy metabolism and the etiology of the Hcy blood level disorder. In addition, we also described various pathological mechanisms induced by hereditary disturbances or nutritional influences and their association with HHcy induced pathology in adults and children and treatment of these metabolic disorders.

Manuka honey attenuates oxidative damage induced by H2O2 in human whole blood in vitro.

Manuka honey has been widely researched regarding its biological properties, in particular its antimicrobial and antioxidant capacities. We tested the genotoxic and genoprotective properties of Manuka honey, ranging from 25-1000 µg/mL, by performing an in vitro comet assay after exposure to human whole blood. No genotoxic effect on whole blood cells was observed within the tested concentration range (p = 0.154). Then, the antigenotoxic potency of Manuka honey against oxidative DNA damage to whole blood cells was assessed. Prior to Manuka honey treatment a modest decrease of H2O2-induced DNA damage was detected in cells, with no statistical significance (p = 0.087). Post-treatment, Manuka honey displayed a stronger potential to attenuate damaged cells at all tested concentrations, with a statistical significant difference (p < 0.001), where concentrations of 25 and 100 µg/mL were most efficient. Manuka honey exhibited a marked potential to protect DNA of whole blood cells from oxidative damage induced by hydrogen peroxide in vitro.

Acute toxicity study in mice of orally administrated TiO2 nanoparticles functionalized with caffeic acid.

The acute toxicity of surface-modified TiO2 nanoparticles (NPs) with caffeic acid (CA) was compared with those of its separate constituents (free CA and bare TiO2 NPs) upon their oral administration in laboratory mice. Prior to in vivo experiments, the interfacial charge transfer (ICT) complex between surface Ti atoms and CA is thoroughly characterized. Composition and stability constants of ICT complex were determined using Job's method and Banesi-Hildebrand analysis, respectively. The experimental data were supported with quantum chemical calculations based on density functional theory (DFT). Acute toxicity signs, including biochemical alterations and extensive histopathological changes in the liver tissue of mice were detected 14 days after oral administration of bare TiO2 NPs. However, the clinical signs of toxicity, the fractional contribution of organs, biochemical parameters of liver and kidney function, and histopathological changes in liver upon treatment with surface-modified TiO2 NPs with CA were not observed. Also, the genotoxic potential of the ICT complex and its constituents were evaluated in leukocytes of whole blood cells in vivo by comet assay. Both, bare and surface-modified TiO2 NPs did not display DNA damaging effect in time frame of 24 h upon their oral administration in mice.