Damage To Biomolecules Research Articles

Radiation Damage in Biomolecules and Cells 2.0

It is well known that ionizing radiation, when it hits living cells, causes a plethora of different damage types at different levels [...].

Molecular Basis of Role of Insulin Resistance in Pathophysiology of Alzheimer’s Disease

Background:The older population in the world is more predisposed to development of diseases linked to oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress including neurodegenerative disease and insulin resistance. Alzheimer’s disease (AD) is the progressive neurodegenerative disease. It contributes to major cause of dementia in older population. Ageing is the most predominant factor in the pathology of AD with 65 years or older age group is more prone to disease. The cognitive impairment is mild in the initial stage of Alzheimer disease but the severity of dementia exacerbates with the progression of AD. The insulin resistance is marked by hyperinsulinemia contributing to glucose intolerance manifesting as chronic hyperglycemia. The cascade of molecular events further triggers reactive oxygen species-mediated oxidative damage of biomolecules. These events subsequently precipitate inflammatory response by immune cells leading to irreversible injury to cells and neurons. Aim & Objective: The aim of the paper is to find out molecular basis of insulin resistance in pathophysiology of Alzheimer’s disease. Present paper reviews various molecular events in insulin resistance that are associated directly or indirectly with the pathophysiology to Alzheimer’s disease. Research Methodology: Research design encompassing critical analysis, qualitative analysis and retrospective research study is followed using secondary data from books, monographs, journals, conference proceedings for the evaluation leading to conclusions beneficial either for future research study or in understanding intricate molecular events between insulin resistance and Alzheimer’s disease. Result: Based on the research design, study revealed several common stressors involved in the pathogenesis of insulin resistance and Alzheimer’s disease. Drug designing targeting stressors could help to ameliorate the severity of Alzheimer disease Originality of Paper: Comprehensive approach was adopted to include papers related to the topic within frame-work of research design to deduce conclusion. Paper Type: Critical analytical review paper

A Lower Serum Antioxidant Capacity as a Distinctive Feature for Women with HER2+ Breast Cancer: A Preliminary Study.

The overexpression of HER2 in breast cancer (BC) can contribute to redox imbalance, which is related to damage and structural modification in many biomolecules. To the best of our knowledge, this is the first study that has investigated the infrared spectrum wavenumbers obtained by ATR-FTIR and their relationship with the levels of redox status markers such as reduced glutathione, superoxide dismutase (SOD), catalase, Ferric Reducing Antioxidant Power (FRAP), and protein carbonyl among women with HER2+ BC, HER2- BC, and benign breast disease (BBD). The study was conducted with 25 women, 17 of whom were diagnosed with BC (6 HER2+ and 11 HER2-) and 8 with BBD. Our results indicate HER2+ BC cases could be distinguished from HER2- BC and BBD cases by their serum's antioxidant capacity [HER2+ BC vs. HER2- BC (AUC = 0.818; specificity = 81.82%; sensitivity = 66.67%); HER2+ BC vs. BBD (AUC = 0.875; specificity = 75%; sensitivity = 83.33%)]. The changes in biochemical terms that occur in serum as a result of the scarcity of antioxidants are related to a peculiar fingerprint in the infrared spectrum obtained by ATR-FTIR. In the serum of women with BBD, the SOD enzyme level is the highest, and this characteristic allowed us to distinguish them from HER2- BC. Finally, data regarding the serological antioxidant capacity of FRAP and the infrared spectrum by ATR-FTIR will allow us to assess biochemical changes that occur before clinical signs, indicating whether changes in therapy or interventions are necessary.

The Relationship between Reactive Oxygen Species and the cGAS/STING Signaling Pathway in the Inflammaging Process

During Inflammaging, a dysregulation of the immune cell functions is generated, and these cells acquire a senescent phenotype with an increase in pro-inflammatory cytokines and ROS. This increase in pro-inflammatory molecules contributes to the chronic inflammation and oxidative damage of biomolecules, classically observed in the Inflammaging process. One of the most critical oxidative damages is generated to the host DNA. Damaged DNA is located out of the natural compartments, such as the nucleus and mitochondria, and is present in the cell's cytoplasm. This DNA localization activates some DNA sensors, such as the cGAS/STING signaling pathway, that induce transcriptional factors involved in increasing inflammatory molecules. Some of the targets of this signaling pathway are the SASPs. SASPs are secreted pro-inflammatory molecules characteristic of the senescent cells and inducers of ROS production. It has been suggested that oxidative damage to nuclear and mitochondrial DNA generates activation of the cGAS/STING pathway, increasing ROS levels induced by SASPs. These additional ROS increase oxidative DNA damage, causing a loop during the Inflammaging. However, the relationship between the cGAS/STING pathway and the increase in ROS during Inflammaging has not been clarified. This review attempt to describe the potential connection between the cGAS/STING pathway and ROS during the Inflammaging process, based on the current literature, as a contribution to the knowledge of the molecular mechanisms that occur and contribute to the development of the considered adaptative Inflammaging process during aging.

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants.

A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson's and Alzheimer's diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the ●OH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor-ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.

Nanobiotechnology-based strategies for enhanced crop stress resilience.

Nanobiotechnology approaches to engineering crops with enhanced stress tolerance may be a safe and sustainable strategy to increase crop yield. Under stress conditions, cellular redox homeostasis is disturbed, resulting in the over-accumulation of reactive oxygen species (ROS) that damage biomolecules (lipids, proteins and DNA) and inhibit crop growth and yield. Delivering ROS-scavenging nanomaterials to plants has been shown to alleviate abiotic stress. Here we review the current state of knowledge of using ROS-scavenging nanomaterials to enhance plant stress tolerance. When present below a threshold level, ROS can mediate redox signalling and defence pathways that foster plant acclimatization against stress. We find that ROS-triggering nanomaterials, such as nanoparticulate silver and copper oxide, have the potential to be judiciously applied to crop species to stimulate the defence system, prime stress responses and subsequently increase the stress resistance of crops.

Analysis of malondialdehyde and ferric reducing ability of plasma in type 2 diabetes mellitus patients in Lucknow city, India

Background: The incidence and prevalence of type 2 diabetes mellitus (T2DM) is increasing due to obesity and sedentary lifestyles. Increased oxidative stress leads to oxidative damage of biomolecules and decreased antioxidant capacity.Aim: The study was designed to determine the malondialdehyde (MDA) and ferric reducing ability of plasma (FRAP) in T2DM patients at IIMS&R Hospital, Lucknow.Method: The oxidative stress was analyzed in T2DM patients as MDA. The total antioxidant capacity was estimated through the FRAP in T2DM patients and control subjects.Results: The level of MDA was observed to be higher (4.84 ± 1.09) in T2DM patients compared to controls (2.20 ± 0.85). The FRAP was lower among T2DM patients (509.46 ± 126.36) compared to controls (895.62 ± 179.92). The difference between FRAP in T2DM patients and controls was statistically significant (p=0.0001).Conclusion: MDA was found to be higher in T2DM, and the FRAP level was lower in T2DM patients compared to controls, signifying increased oxidative stress and decreased antioxidant level in T2DM patients.

487 Lipidomic and proteomic analyses identify increased degradation of sphingolipids in prematurely senescent human dermal fibroblasts

A wide range of environmental factors (e.g. UV radiation, pollution) challenges skin homeostasis and its prolonged imbalance accelerates skin aging. Aged skin is characterized by presence of senescent cells, which have a changed appearance and phenotype, accumulate damaged biomolecules and simultaneously produce a mixture of danger signaling molecules which negatively affect their microenvironment and activate the immune response. We previously described increased levels of lysophosphatidylcholines, in both replicative senescent and in in vitro stress-induced premature senescent (SIPS) fibroblasts.

COMPREHENSIVE MOLECULAR STUDY REVEALS THE POTENTIAL ROLE OF CHEBULINIC ACID AND BOERAVINONE B TO ESTABLISH REDOX HOMEOSTASIS IN METABOLICALLY STRESSED CELLS

Objective: Our objective was to assess the multi-dimensional protective mechanism of Chebulinic acid (CA) and Boeravinone B (BB) against MG-induced metabolic stress and cytotoxicity. Methods: In this study, we have studied CA-and BB-mediated changes in molecular markers of highly dynamic mechanisms of mitochondrial disintegration, nuclear damage and cell death pathways associated with early ageing in MG-exposed Saccharomyces cerevisiae cells using biochemical assays, qRT-PCR and flow cytometry. Results: We found that CA and BB interventions during MG-induced stress in S. cerevisiae reduce the rate of extracellular nitrite production, protein carbonyl content, lipid peroxidation and in addition, photo components positively modulate the expression patterns of genes involved in different cell death pathways. Furthermore, CA and BB treatments to MG-stressed cells reduced the number of cells in late apoptosis by 13.4% and 28.3%, respectively. On top of that, CA and BB supplementation during MG-stress restored mitochondrial membrane potential (ΔΨm) by 63.0% and 62.5%, respectively. Conclusion: Based on the results of this study, it seems CA and BB phytotherapy protect against MG-induced cytotoxicity through their natural antioxidant properties by establishing redox homeostasis; thus, CA and BB defend the cell components from oxidative damage of different biomolecules and organelles, ultimately increase longevity.

Anti-tumor and antioxidant activity of kaempferol-3-O-alpha-L-rhamnoside (Afzelin) isolated from Pithecellobium dulce leaves

BackgroundPithecellobium dulce (Roxb.), an evergreen medium-sized, spiny tree which have vast nutritional values and widely used in ayurvedic medicines and home remedies. The plant has also been a rich source of biologically active compounds. The present study was designed to isolate pure compound from ethyl acetate fraction of methanol extract of leaves and to know the efficacy as antioxidant as well as its anti-tumor activity on Ehrlich ascites carcinoma cell (EAC). MethodsThe leaves were extracted with methanol and fractionated with different solvents. The isolation of the compound was carried out by column chromatography from ethyl acetate fraction (EAF) and structure was revealed by 1H-NMR and 13C NMR. The antioxidant activity was investigated by the scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals as well as the inhibition of oxidative damage of pUC19 plasmid DNA, hemolysis and lipid peroxidation induced by a water-soluble free radical initiator 2,2’-azo (2-asmidinopropane) dihydrochloride (AAPH) in human erythrocytes. In vivo anti-tumor activity of the compound was also evaluated by determining the viable tumor cell count, hematological profiles of experimental mice along with observing morphological changes of EAC cells by fluorescence microscope.ResultsThe isolated compound kaempferol-3-O-alpha-L-rhamnoside effectively inhibited AAPH induced oxidation in DNA and human erythrocyte model and lipid per oxidation as well as a stronger DPPH radical scavenging activity. In anti-tumor assay, at a dose of 50 mg/kg body weight exhibit about 70.89 ± 6.62% EAC cell growth inhibition, whereas standard anticancer drug vincristine showed 77.84 ± 6.69% growth inhibition.ConclusionThe compound may have a great importance as a therapeutic agent in preventing oxidative damage of biomolecules and therapeutic use in chemotherapy.

Effects of tributyrin on the growth performance, immune response and intestinal microbiota of shrimp (Litopenaeus vannamei)

The present study aimed to evaluate the effects of tributyrin (TB)on the growth performance, intestinal immune and microbiota of shrimp (Litopenaeus vannamei). A total of 720 healthy shrimp (0.88 ± 0.02 g) were fed with four different diets supplemented with 0, 500, 1000, and 1500 mg/kg of TB for 42 days. The current results showed that 1500 mg/kg TB dietary have positive impacts on growth performance and digestive enzymes activity, increasing the content of whole-body crude protein and lipid. In addition, TB supplement improved the intestine healthy with two possible mechanisms. 1) TB inhibited biomolecule damages including lipid peroxidation and protein carbonyl by improves antioxidant capacity 2) TB inhibited the expression level of TNF-α and IL-16 genes to attenuate inflammatory response by regulating the NF-kB activation of intestine. As for the intestinal microbiota, the microbial diversity and richness decreased and the abundance of potential probiotic (Rhodobacteraceae, Pseudomonas) increased in TB groups. The present results suggested that TB could be used as nutritional supplement to improve intestinal health of shrimp.

Redox signaling at the crossroads of human health anddisease.

Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double‐edged sword in disease progression suggest two different therapeutic strategies to treat redox‐relevant diseases, in which targeting ROS sources and redox‐related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox‐relevant diseases.

Differences in advanced glycation endproducts (AGEs) in plasma from birds and mammals of different body sizes and ages

Birds and mammals provide a physiological paradox: similar-sized mammals live shorter lives than birds; yet, birds have higher blood glucose concentrations than mammals, and higher basal metabolic rates. We have previously shown that oxidative stress patterns between mammals and birds differ, so that birds, generally, have lower blood antioxidant capacity, and lower lipid peroxidation concentration. There is a close association between oxidative stress and the production of carbohydrate-based damaged biomolecules, Advanced Glycation End-products (AGEs). In mammals, AGEs can bind to their receptor (RAGE), which can lead to increases in reactive oxygen species (ROS) production, and can decrease antioxidant capacity. Here, we used plasma from birds and mammals to address whether blood plasma AGE-BSA concentration is associated with body mass and age in these two groups. We found a statistically significantly higher average concentrations of AGE-BSA in birds compared with mammals, and we found a significantly positive correlation between AGE-BSA and age in mammals, though, this correlation disappeared after phylogenetic correction. We propose that the higher AGE concentration in birds is mainly attributable to greater AGE-production due to elevated basal glucose concentrations and decreased AGE-clearance given differences in glomerular filtration rates in birds compared with mammals. Additionally, due to the potential lack of an AGE receptor in birds, AGE accumulation may not be closely linked to oxidative stress and therefore pose a lesser physiological challenge in birds compared to mammals.

Nicotine as a Catalyst for Chlorination Promoted by Hypochlorous Acid: Experimental and Theoretical Studies

There is robust evidence of the hypochlorous acid (HClO)-mediated damage in biomolecules, and nicotine boosts the chlorination potency of HClO. We present experimental and theoretical evidence of the mechanism by which nicotine catalyzes the chlorination of pyranine. The rate constants for chlorination of pyranine by HClO were measured in the presence (5.3 × 105 mol‑1 L s-1) and absence of nicotine (4.2 × 103 mol-1 L s-1), revealing the catalytic effect of the alkaloid. Density functional theory (DFT) calculations, based on B3LYP-GD3(BJ)/6-311++G(3df,2p)/ SMD(Water)//B3LYP-GD3(BJ)/6-311++G(2d,p)/SMD(Water) level of theory, were performed and showed a decreased activation energy for chlorine transfer and hydrogen abstraction when nicotine chloramine intermediated the reaction. The atomic polar tensor (APT) charges on the chlorine atom of HClO (+0.084) were lower than the chlorine of nicotine chloramine (+0.149), revealing the higher electrophilic character of nicotine chloramine. In conclusion, the increased electrophilic nature of HClO provoked by nicotine explains its catalytic effect.

Protocols to Measure Oxidative Stress and DNA Damage in Asthma.

Asthma is associated with oxidative stress and oxidative damage of biomolecules, including DNA. Here, we describe the protocols to quantify reactive oxygen species (ROS) and oxidative stress markers in a mouse model of allergic airway inflammation. We also provide detailed methods to measure DNA damage by long-run real-time PCR for DNA-damage quantification (LORD-Q) assay and gene-specific DNA damage analyses by long amplicon (LA)-qPCR. Additionally, we describe methods to quantify oxidized DNA base lesions in lung genomic DNA by mass spectrometry, and to measure enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1). Using these methods, the levels of oxidative stress and DNA damage in allergic inflammation and asthma can be elucidated.

Flower‐Like Nanozymes with Large Accessibility of Single Atom Catalysis Sites for ROS Generation Boosted Tumor Therapy

AbstractThe use of reactive oxygen species (ROS) generators based on single‐atom catalysts (SACs) has been an emerging strategy for mediating tumor therapy, however, the current systems suffer from low mass transport efficiency. Here, a novel strategy of morphology fragmentation is developed to fabricate flower‐like SAC nanozymes with greatly improved 3D accessibility of active sites. Specifically, the coordinationally polymerized zeolite imidazole framework acts as a polyphenol oxidase‐like enzyme to catalyze the in situ polymerization of polydopamine (PDA) which leads to blockage of micropores and crosslinking of the morphology‐deteriorated ZIF nanosheets. The protective carbonization by PDA results in SAC nanozymes (C‐NFs) with plenty of reopened micropores and defect mesopores (≈4 nm) in the nanopetals, large interpetal pore space (≈39 nm), high surface area (388 m2 g−1), as well as an ultrahigh loading metal atoms (27.3 wt%). Subsequently, a superior peroxidases‐like activity (36.6‐fold increment in the turnover frequency) facilitates significantly strengthened ROS generation and damage of biomolecules. Moreover, the employment of apoferritin modification/loading leads to particle dispersion in solution and concomitant drug loading. The following cancer cell re‐sensitization is proven to be advantageous for boosting ROS‐facilitated treatment of drug‐resistant tumors, opening up new avenues for ROS therapy.

Antioxidant Activity of Total phenols and Flavonoids extracted from Echinops polyceras roots grown in Syria

Free radicals are reactive compounds, their excessive production is considered to be an important cause of oxidative damage in biomolecules causing degenerative diseases. Polyphenols are one of the most important groups of secondary metabolites of plants, which have an antioxidant activity depending on their properties as hydrogen donors. Echinops polyceras Boiss. (Asteraceae) is one of Echinops genus species that spread in Syria, Lebanon, and Palestine. Phytochemicals found in this species leaves have been extracted with gradient polarity solvents, and primary screening of the secondary metabolites was established. The phenolic compounds and flavonoids contents were determined. The free radicals scavenging activity was evaluated for all extracts with DPPH• in a 96-well microplate. The specificity study indicates that ascorbic acid was absent, and reducing sugars were exist in the aqueous extract. The identification tests showed the presence of polyphenols like flavonoids and coumarins. The methanolic extract of the E. polyceras leaves was the most effective scavengers of free radicals (90.22% in 30 min) with phenolic compounds content 682.5 mg GAE/g of dried extract (DE) and flavonoids content 194.5 mg QE/ g DE. The chloroform extract was the least effective as free radical scavenging (60% in 30 min) as the phenolic compounds content was 278.5 mg GAE/g DE and flavonoids content 94 mg QE/ g DE. In conclusion, the phenolic compounds and flavonoids from Echinops polyceras Boiss. are effective in free radicals scavenging and protecting from diseases caused by oxidative stress.

125 Extended (epi-)lidomic analysis of senescent dermal fibroblasts

Skin as a barrier separates and protects organism from its surrounding. A wide range of stressors from the environment (UV radiation, pollution) challenges skin homeostasis and prolonged imbalance accelerates skin aging. Aged skin is characterized by presence of senescent cells, which have changed appearance and phenotype, accumulate damaged biomolecules (DNA, proteome, lipidome) and simultaneously produce a mixture of danger signaling molecules – so called senescent associated secretory phenotype (SASP). This concoction of biomolecules – including lipids - influences cell microenvironment and the immune system towards a low grade chronic inflammatory phenotype. We previously described increased levels of lysophosphatidylcholines, in both replicative senescent fibroblast and in in vitro stress-induced premature senescent (SIPS) fibroblasts. Using UHPLC triple quadrupole MS/MS method we identified additional lysophospholipid species regulated upon hydrogen peroxide or doxorubicin SIPS protocols. Upon both treatments lipid categories of lysophosphatidylcholines and lysophosphatidylethanolamines were significantly elevated in comparison to corresponding controls, however the effect was more striking in doxorubicin-induced senescent fibroblasts. Moreover, a broader spectrum of analyzed lipid classes revealed that phospholipids are not only lipids which are senescence regulated. There were apparent changes between above mentioned SIPS protocols, suggesting a different involvement of enzymatically or reactive oxygen species mediated lipids metabolism. Recognition of structure and function of (epi-)lipidome could contribute to better understanding of mechanism of SAPS driven continuous activation of immune system and therefore to help find approaches how to mitigate/ prevent development of associated skin pathologies.

Oxidative Stress in Mucopolysaccharidoses: Pharmacological Implications.

Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is crucial but is not the only pathomechanism of these severe, inherited metabolic diseases. Among various factors and processes influencing the course of MPS, oxidative stress appears to be a major one. Oxidative imbalance, occurring in MPS and resulting in increased levels of reactive oxidative species, causes damage of various biomolecules, leading to worsening of symptoms, especially in the central nervous system (but not restricted to this system). A few therapeutic options are available for some types of MPS, including enzyme replacement therapy and hematopoietic stem cell transplantation, however, none of them are fully effective in reducing all symptoms. A possibility that molecules with antioxidative activities might be useful accompanying drugs, administered together with other therapies, is discussed in light of the potential efficacy of MPS treatment.

Ameliorating effects of white mulberry on iron-overload-induced oxidative stress and liver fibrosis in Swiss albino mice

Excess iron causes oxidative damage of biomolecules, leading to tissue injury primarily liver failure. In this study, we explored the remediating effects of Morus alba L. (MAME) on iron-overload-induced oxidative stress and liver injury in mice. The In vitro study revealed the antioxidant and free radical scavenging properties of MAME. Intraperitoneal injection of iron-dextran was administered in Swiss albino mice to induce iron-overload condition and the mice were further treated with MAME. MAME treatment significantly decreased liver iron, serum ferritin level, oxidative stress, and restored serum parameters and liver antioxidants. Moreover, biochemical and histopathological analyses confirmed the alleviated liver damage and fibrosis upon MAME treatment. The protective effect of MAME against iron-overload-induced apoptosis was confirmed by upregulation of protein levels of Bax, Caspase-3, and PARP. The treatment also affected the expression of MAPKs (ERK, JNK, and p38). GC-MS analysis revealed the presence of various bioactive phytochemicals in MAME that may be responsible for ameliorating effects of excess iron. Thus MAME can be envisaged as an effective iron chelator in the treatment of iron-overload-induced liver injury and fibrosis.