Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized for playing a dual role, since they can be either deleterious or beneficial to biological systems. An imbalance between ROS production and elimination is termed oxidative stress, a critical factor and common denominator of many chronic diseases such as cancer, cardiovascular diseases, metabolic diseases, neurological disorders (Alzheimer's and Parkinson's diseases), and other disorders. To counteract the harmful effects of ROS, organisms have evolved a complex, three-line antioxidant defense system. The first-line defense mechanism is the most efficient and involves antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). This line of defense plays an irreplaceable role in the dismutation of superoxide radicals (O2•-) and hydrogen peroxide (H2O2). The removal of superoxide radicals by SOD prevents the formation of the much more damaging peroxynitrite ONOO- (O2•- + NO• → ONOO-) and maintains the physiologically relevant level of nitric oxide (NO•), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., ß-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion.

Antioxidant, Antiglaucoma, Anticholinergic, and Antidiabetic Effects of Kiwifruit (Actinidia deliciosa) Oil: Metabolite Profile Analysis Using LC-HR/MS, GC/MS and GC-FID.

Determining the antioxidant abilities and enzyme inhibition profiles of medicinally important plants and their oils is of great importance for a healthy life and the treatment of some common global diseases. Kiwifruit (Actinidia deliciosa) oil was examined and researched using several bioanalytical methods comprehensively for the first time in this research to determine its antioxidant, antiglaucoma, antidiabetic and anti-Alzheimer's capabilities. Additionally, the kiwifruit oil inhibitory effects on acetylcholinesterase (AChE), carbonic anhydrase II (CA II), and α-amylase, which are linked to a number of metabolic illnesses, were established. Furthermore, LC-HRMS analysis was used to assess the phenolic content of kiwifruit oil. It came to light that kiwifruit oil contained 26 different phenolic compounds. According to the LC-HRMS findings, kiwifruit oil is abundant in apigenin (74.24 mg/L oil), epigallocatechin (12.89 mg/L oil), caryophyllene oxide (12.89 mg/L oil), and luteolin (5.49 mg/L oil). In addition, GC-MS and GC-FID studies were used to ascertain the quantity and chemical composition of the essential oils contained in kiwifruit oil. Squalene (53.04%), linoleoyl chloride (20.28%), linoleic acid (2.67%), and palmitic acid (1.54%) were the most abundant compounds in kiwifruit oil. For radical scavenging activities of kiwifruit oil, 1,1-diphenyl-2-picryl-hydrazil (DPPH•) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS•+) radicals scavenging techniques were examined. These methods effectively demonstrated the potent radical scavenging properties of kiwifruit oil (IC50: 48.55 µg/mL for DPPH•, and IC50: 77.00 µg/mL for ABTS•+ scavenging). Also, for reducing capabilities, iron (Fe3+), copper (Cu2+), and Fe3+-2,4,6-tri(2-pyridyl)-S-triazine (TPTZ) reducing abilities were studied. Moreover, kiwifruit oil showed a considerable inhibition effect towards hCA II (IC50: 505.83 µg/mL), AChE (IC50: 12.80 µg/mL), and α-amylase (IC50: 421.02 µg/mL). The results revealed that the use of kiwifruit oil in a pharmaceutical procedure has very important effects due to its antioxidant, anti-Alzheimer, antidiabetic, and antiglaucoma effects.

Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging.

A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.

The role of redox active copper(II) on antioxidant properties of the flavonoid baicalein: DNA protection under Cu(II)-Fenton reaction and Cu(II)-ascorbate system conditions.

The antioxidant properties of flavonoids are mediated by their functional hydroxyl groups, which are capable of both chelating redox active metals such as iron, copper and scavenging free radicals. In this paper, the antioxidant vs. prooxidant and DNA protecting properties of baicalein and Cu(II)-baicalein complexes were studied under the conditions of the Copper-Fenton reaction and of the Copper-Ascorbate system. From the relevant EPR spectra, the interaction of baicalein with Cu(II) ions was confirmed, while UV-vis spectroscopy demonstrated a greater stability over time of Cu(II)-baicalein complexes in DMSO than in methanol and PBS and Phosphate buffers. An ABTS study confirmed a moderate ROS scavenging efficiency, at around 37%, for both free baicalein and Cu(II)-baicalein complexes (in the ratios 1:1 and 1:2). The results from absorption titrations are in agreement with those from viscometric studies and confirmed that the binding mode between DNA and both free baicalein and Cu-baicalein complexes, involves hydrogen bonds and van der Waals interactions. The DNA protective effect of baicalein has been investigated by means of gel electrophoresis under the conditions of the Cu-catalyzed Fenton reaction and of the Cu-Ascorbate system. In both cases, it was found that, at sufficiently high concentrations, baicalein offers some protection to cells from DNA damage caused by ROS (singlet oxygen, hydroxyl radicals and superoxide radical anions). Accordingly, baicalein may be useful as a therapeutic agent in diseases with a disturbed metabolism of redox metals such as copper, for example Alzheimer's disease, Wilson's disease and various cancers. While therapeutically sufficient concentrations of baicalein may protect neuronal cells from Cu-Fenton-induced DNA damage in regard to neurological conditions, conversely, in the case of cancers, low concentrations of baicalein do not inhibit the pro-oxidant effect of copper ions and ascorbate, which can, in turn, deliver an effective damage to DNA in tumour cells.

Comprehensive Metabolite Profiling of Berdav Propolis Using LC-MS/MS: Determination of Antioxidant, Anticholinergic, Antiglaucoma, and Antidiabetic Effects.

Propolis is a complex natural compound that honeybees obtain from plants and contributes to hive safety. It is rich in phenolic and flavonoid compounds, which contain antioxidant, antimicrobial, and anticancer properties. In this study, the chemical composition and antioxidant activities of propolis were investigated; ABTS•+, DPPH• and DMPD•+ were prepared using radical scavenging antioxidant methods. The phenolic and flavonoid contents of propolis were 53 mg of gallic acid equivalent (GAE)/g and 170.164 mg of quercetin equivalent (QE)/g, respectively. The ferric ion (Fe3+) reduction, CUPRAC and FRAP reduction capacities were also studied. The antioxidant and reducing capacities of propolis were compared with those of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol and Trolox reference standards. The half maximal inhibition concentration (IC50) values of propolis for ABTS•+, DPPH• and DMPD•+ scavenging activities were found to be 8.15, 20.55 and 86.64 µg/mL, respectively. Propolis extract demonstrated IC50 values of 3.7, 3.4 and 19.6 µg/mL against α-glycosidase, acetylcholinesterase (AChE) and carbonic anhydrase II (hCA II) enzyme, respectively. These enzymes' inhibition was associated with diabetes, Alzheimer's disease (AD) and glaucoma. The reducing power, antioxidant activity and enzyme inhibition capacity of propolis extract were comparable to those demonstrated by the standards. Twenty-eight phenolic compounds, including acacetin, caffeic acid, p-coumaric acid, naringenin, chrysin, quinic acid, quercetin, and ferulic acid, were determined by LC-MS/MS to be major organic compounds in propolis. The polyphenolic antioxidant-rich content of the ethanol extract of propolis appears to be a natural product that can be used in the treatment of diabetes, AD, glaucoma, epilepsy, and cancerous diseases.

Comprehensive Metabolite Profiling of Cinnamon (Cinnamomum zeylanicum) Leaf Oil Using LC-HR/MS, GC/MS, and GC-FID: Determination of Antiglaucoma, Antioxidant, Anticholinergic, and Antidiabetic Profiles.

In this study, for the first time, the antioxidant and antidiabetic properties of the essential oil from cinnamon (Cinnamomum zeylanicum) leaves were evaluated and investigated using various bioanalytical methods. In addition, the inhibitory effects of cinnamon oil on carbonic anhydrase II (hCA II), acetylcholinesterase (AChE), and α-amylase, which are associated with various metabolic diseases, were determined. Further, the phenolic contents of the essential oil were determined using LC-HRMS chromatography. Twenty-seven phenolic molecules were detected in cinnamon oil. Moreover, the amount and chemical profile of the essential oils present in cinnamon oil was determined using GC/MS and GC-FID analyses. (E)-cinnamaldehyde (72.98%), benzyl benzoate (4.01%), and trans-Cinnamyl acetate (3.36%) were the most common essential oils in cinnamon leaf oil. The radical scavenging activities of cinnamon oil were investigated using 1,1-diphenyl-2-picryl-hydrazil (DPPH•), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), and (ABTS•+) bioanalytical scavenging methods, which revealed its strong radical scavenging abilities (DPPH•, IC50: 4.78 µg/mL; and ABTS•+, IC50: 5.21 µg/mL). Similarly, the reducing capacities for iron (Fe3+), copper (Cu2+), and Fe3+-2,4,6-tri(2-pyridyl)-S-triazine (TPTZ) were investigated. Cinnamon oil also exhibited highly effective inhibition against hCA II (IC50: 243.24 µg/mL), AChE (IC50: 16.03 µg/mL), and α-amylase (IC50: 7.54µg/mL). This multidisciplinary study will be useful and pave the way for further studies for the determination of antioxidant properties and enzyme inhibition profiles of medically and industrially important plants and their oils.

Sahlep (Dactylorhiza osmanica): Phytochemical Analyses by LC-HRMS, Molecular Docking, Antioxidant Activity, and Enzyme Inhibition Profiles.

Studies have shown an inverse correlation among age-related illnesses like coronary heart disease and cancer and intake of fruit and vegetable. Given the probable health benefits of natural antioxidants from plants, research on them has increased. Dactylorhiza osmanica is consumed as a food and traditional medicine plant in some regions of Turkey, so evaluation of the biological ability of this species is important. In this study, the amount of phenolic content (LC-HRMS), antioxidant activities and enzyme inhibitory properties of an endemic plant, D. osmanica, were investigated. The antioxidant capacities of an ethanol extract of D. osmanica aerial parts (EDOA) and roots (EDOR) were evaluated with various antioxidant methods. Additionally, the enzyme inhibitory effects of EDOA and EDOR were examined against acetylcholinesterase (AChE), α-glycosidase, and α-amylase enzymes, which are associated with common and global Alzheimer's disease and diabetes mellitus. The IC50 values of EDOA against the enzymes were found to be 1.809, 1.098, and 0.726 mg/mL, respectively; and the IC50 values of EDOR against the enzymes were found to be 2.466, 0.442, and 0.415 mg/mL, respectively. Additionally, LC-HRMS analyses revealed p-Coumaric acid as the most plentiful phenolic in both EDOA (541.49 mg/g) and EDOR (559.22 mg/g). Furthermore, the molecular docking interaction of p-coumaric acid, quercitrin, and vanillic acid, which are the most plentiful phenolic compounds in the extracts, with AChE, α-glucosidase, and α-amylase, were evaluated using AutoDock Vina software. The rich phenolic content and the effective antioxidant ability and enzyme inhibition potentials of EDOA and EDOR may support the plant's widespread food and traditional medicinal uses.

Essential metals in health and disease.

In total, twenty elements appear to be essential for the correct functioning of the human body, half of which are metals and half are non-metals. Among those metals that are currently considered to be essential for normal biological functioning are four main group elements, sodium (Na), potassium (K), magnesium (Mg), and calcium (Ca), and six d-block transition metal elements, manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn) and molybdenum (Mo). Cells have developed various metallo-regulatory mechanisms for maintaining a necessary homeostasis of metal-ions for diverse cellular processes, most importantly in the central nervous system. Since redox active transition metals (for example Fe and Cu) may participate in electron transfer reactions, their homeostasis must be carefully controlled. The catalytic behaviour of redox metals which have escaped control, e.g. via the Fenton reaction, results in the formation of reactive hydroxyl radicals, which may cause damage to DNA, proteins and membranes. Transition metals are integral parts of the active centers of numerous enzymes (e.g. Cu,Zn-SOD, Mn-SOD, Catalase) which catalyze chemical reactions at physiologically compatible rates. Either a deficiency, or an excess of essential metals may result in various disease states arising in an organism. Some typical ailments that are characterized by a disturbed homeostasis of redox active metals include neurological disorders (Alzheimer's, Parkinson's and Huntington's disorders), mental health problems, cardiovascular diseases, cancer, and diabetes. To comprehend more deeply the mechanisms by which essential metals, acting either alone or in combination, and/or through their interaction with non-essential metals (e.g. chromium) function in biological systems will require the application of a broader, more interdisciplinary approach than has mainly been used so far. It is clear that a stronger cooperation between bioinorganic chemists and biophysicists - who have already achieved great success in understanding the structure and role of metalloenzymes in living systems - with biologists, will access new avenues of research in the systems biology of metal ions. With this in mind, the present paper reviews selected chemical and biological aspects of metal ions and their possible interactions in living systems under normal and pathological conditions.

Polyphenol Contents, Potential Antioxidant, Anticholinergic and Antidiabetic Properties of Mountain Mint (Cyclotrichium leucotrichum).

In the present work, antioxidant and antidiabetic potentials of mountain mint [Cyclotrichium leu-cotrichum (Stapf ex Rech. Fil.) Leblebici] was the first time appraised. In this sense, methanol (MECL) and water (WECL) extracts were obtained from aerial parts of mountain mint (Cyclotrichium leucotrichum) and studied for their antioxidant ability by several bioanalytical assays. Also, their inhibition profiles were realized toward several metabolic enzymes connected to some diseases, including butyrylcholinesterase (BChE), α-glycosidase, acetylcholinesterase (AChE), and α-amylase enzymes. Additionally, their phenolic contents were determined by putative chromatographic method of LC/MS/MS. Consequently, nineteen phenolic molecules were identified in MECL and fifteen phenolic molecules were found in WECL. Also, antioxidant effects of both extracts were studied using by the methods of 1,1-diphenyl-2-picryl-hydrazyl (DPPH⋅), 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS.+ ) and N,N-dimethyl-p-phenylenediamine (DMPD.+ ) scavenging activities, ferric (Fe3+ ) and cupric (Cu2+ ) ions and Fe3+ -2,4,6-tri(2-pyridyl)-s-triazine (TPTZ) reducing capacities. MECL and WECL were found as powerful DPPH⋅ (IC50 : 23.74 and 28.85 µg/mL), ABTS.+ (IC50 : 12.53 and 14.05 µg/mL) and DMPD.+ scavenging effects (IC50 : 43.52 and 54.80 µg/mL). Also, both extracts demonstrated the effective inhibition on AChE (IC50 : 69.31 and 115.51 µg/mL), BChE (IC50 : 57.75 and 86.62 µg/mL), α-glycosidase (IC50 : 36.47 and 62.94 µg/mL) and α-amylase (IC50 : 1.01 and 3.43 µg/mL). This study will be useful for future studies to determine the antioxidant properties and enzyme inhibition profile of food, medical and industrially important plants.

The effect of Luteolin on DNA damage mediated by a copper catalyzed Fenton reaction.

Luteolin has been reviewed as a flavonoid possessing potential cardioprotective, anti-inflammatory, anti-cancer activities. Having multiple biological effects, luteolin may act as either an antioxidant or a pro-oxidant. In this work, the protective role of copper(II)-chelation by luteolin on DNA damage via the Cu-Fenton reaction was studied. EPR and UV-vis spectroscopic data demonstrated that the luteolin, lacking 3-OH group, chelates to Cu(II) via the 5-OH and 4-CO groups, respectively. EPR spin trapping experiments using DMPO spin trap confirmed that the coordination of luteolin to Cu(II) significantly suppressed formation of hydroxyl and superoxide radicals (by 80%) in a Cu-Fenton system. Absorption titrations showed that the chelation of Cu(II) by luteolin slightly increased the mild intercalation strength of its interaction with DNA, as compared with free luteolin. Comparison with kaempferol and quercetin revealed, that the strength of the interaction between the free flavonoids/Cu-flavonoid complexes with DNA is only mildly affected by the presence/absence of 3-OH group. Due to the differences in the sensitivities of absorption titrations and viscometry, the latter confirmed weaker DNA intercalating efficiency of Cu-luteolin complex than does free luteolin. A dose dependent protective effect of luteolin against ROS-induced DNA damage was observed using gel electrophoresis. This effect was more pronounced compared to quercetin and kaempferol. In conclusion, the administration of luteolin to patients suffering from oxidative stress-related diseases with disturbed Cu-metabolism such as Alzheimer's diseases (antioxidant effect) and certain cancers (prooxidant effect) may have several health benefits.

Gestational diabetes mellitus induces placental vasculopathies.

Gestational diabetes mellitus (GDM) poses significant long- and short-term risks to both the developing fetus and the mother. GDM can lead to maternal complications during pregnancy and increase the mother's risk of developing type 2 diabetes mellitus and cardiovascular disease later. The present study aimed to evaluate the maternal and fetal vasculopathies in the placenta of Saudi women with GDM. This prospective study examined 84 placentas from full-term pregnant women with no complications other than GDM; 40 placentas were collected from healthy women (controls), and 44 were collected from women diagnosed with GDM. The sampling took place in King Saud University Medical City, Riyadh, between January and August 2019. All placentas were histologically examined according to the Amsterdam Placental Workshop Group (2014, 2015). The results showed that the most common placental changes on the maternal side of the placenta in the GDM group were significant syncytial knots (77%), calcification (70%), villous agglutination (57%), decidual vasculopathy (43%), and retroplacental hemorrhage (34%). Placental infarction was the least common placental change in both groups. On the fetal side, vasculopathies included significant villous fibrinoid necrosis (70.5%), chorangiosis (50%), fibromuscular sclerosis (50%), and villous edema (38.6%). Significant villous fibrinoid necrosis, villous edema, and significant fibromuscular sclerosis were more prevalent in the GDM group. The present study concluded that gestational diabetes mellitus induces histopathological phenotypes in the full-term placenta. Increased decidual vasculopathy, syncytial knots, retroplacental hemorrhage, classification, villous agglutination, chorangiosis, villous edema, villous fibroid necrosis, and fibromuscular sclerosis may indicate GDM in the mother. Such findings in the placenta of a woman who has not been diagnosed with GDM increase the need for GDM examination in future pregnancies.

Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes.

The agenda of pharmacology discovery in the field of personalized oncology was dictated by the search of molecular targets assumed to deterministically drive tumor development. In this perspective, genes play a fundamental "causal" role while cells simply act as causal proxies, i.e., an intermediate between the molecular input and the organismal output. However, the ceaseless genomic change occurring across time within the same primary and metastatic tumor has broken the hope of a personalized treatment based only upon genomic fingerprint. Indeed, current models are unable in capturing the unfathomable complexity behind the outbreak of a disease, as they discard the contribution of non-genetic factors, environment constraints, and the interplay among different tiers of organization. Herein, we posit that a comprehensive personalized model should view at the disease as a "historical" process, in which different spatially and timely distributed factors interact with each other across multiple levels of organization, which collectively interact with a dynamic gene-expression pattern. Given that a disease is a dynamic, non-linear process - and not a static-stable condition - treatments should be tailored according to the "timing-frame" of each condition. This approach can help in detecting those critical transitions through which the system can access different attractors leading ultimately to diverse outcomes - from a pre-disease state to an overt illness or, alternatively, to recovery. Identification of such tipping points can substantiate the predictive and the preventive ambition of the Predictive, Preventive and Personalized Medicine (PPPM/3PM). However, an unusual effort is required to conjugate multi-omics approaches, data collection, and network analysis reconstruction (eventually involving innovative Artificial Intelligent tools) to recognize the critical phases and the relevant targets, which could help in patient stratification and therapy personalization.

Antidiabetic, anticholinergic and antioxidant activities of aerial parts of shaggy bindweed (Convulvulus betonicifolia Miller subsp.) - profiling of phenolic compounds by LC-HRMS.

In order to evaluate the antioxidant activity of evaporated ethanolic extract (EESB) and lyophilized water extract (WESB) of Shaggy bindweed (Convulvulus betonicifolia Mill. Subs), some putative antioxidant methods such as DPPH· scavenging activity, ABTS•+ scavenging effect, ferric ions (Fe3+) reduction method, cupric ions (Cu2+) reducing capacity, and ferrous ions (Fe2+) binding activities were separately performed. Also, ascorbic acid, α-tocopherol and BHT were used as the standard compounds. Additionally, some phenolic compounds that responsible for antioxidant abilities of EESB and WESB were screened by liquid chromatography-high resolution mass spectrometry (LC-HRMS). At the same concentration, EESB and WESB demonstrated effective antioxidant abilities when compared to standards. In addition, EESB demonstrated IC50 values of 1.946 µg/mL against acetylcholinesterase (AChE), 0.815 µg/mL against α-glycosidase and 0.675 µg/mL against α-amylase enzymes.

LC-HRMS Profiling and Antidiabetic, Anticholinergic, and Antioxidant Activities of Aerial Parts of Kinkor (Ferulago stellata).

Kinkor (Ferulago stellata) is Turkish medicinal plant species and used in folk medicine against some diseases. As far as we know, the data are not available on the biological activities and chemical composition of this medicinal plant. In this study, the phytochemical composition; some metabolic enzyme inhibition; and antidiabetic, anticholinergic, and antioxidant activities of this plant were assessed. In order to evaluate the antioxidant activity of evaporated ethanolic extract (EEFS) and lyophilized water extract (WEFS) of kinkor (Ferulago stellata), some putative antioxidant methods such as DPPH· scavenging activity, ABTS•+ scavenging activity, ferric ions (Fe3+) reduction method, cupric ions (Cu2+) reducing capacity, and ferrous ions (Fe2+)-binding activities were separately performed. Furthermore, ascorbic acid, BHT, and α-tocopherol were used as the standard compounds. Additionally, the main phenolic compounds that are responsible for antioxidant abilities of ethanol and water extracts of kinkor (Ferulago stellata) were determined by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Ethanol and water extracts of kinkor (Ferulago stellata) demonstrated effective antioxidant abilities when compared to standards. Moreover, ethanol extract of kinkor (Ferulago stellata) demonstrated IC50 values of 1.772 µg/mL against acetylcholinesterase (AChE), 33.56 ± 2.96 µg/mL against α-glycosidase, and 0.639 µg/mL against α-amylase enzyme respectively.

Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study.

Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer's disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu-kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer's disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders.

Survival Pathways Are Differently Affected by Microgravity in Normal and Cancerous Breast Cells.

Metazoan living cells exposed to microgravity undergo dramatic changes in morphological and biological properties, which ultimately lead to apoptosis and phenotype reprogramming. However, apoptosis can occur at very different rates depending on the experimental model, and in some cases, cells seem to be paradoxically protected from programmed cell death during weightlessness. These controversial results can be explained by considering the notion that the behavior of adherent cells dramatically diverges in respect to that of detached cells, organized into organoids-like, floating structures. We investigated both normal (MCF10A) and cancerous (MCF-7) breast cells and found that appreciable apoptosis occurs only after 72 h in MCF-7 cells growing in organoid-like structures, in which major modifications of cytoskeleton components were observed. Indeed, preserving cell attachment to the substrate allows cells to upregulate distinct Akt- and ERK-dependent pathways in MCF-7 and MCF-10A cells, respectively. These findings show that survival strategies may differ between cell types but cannot provide sufficient protection against weightlessness-induced apoptosis alone if adhesion to the substrate is perturbed.

The biological activities, molecular docking studies, and anticancer effects of 1-arylsuphonylpyrazole derivatives.

This work is devoted to definition of the direction of reaction between 1-benzenesulfonylimino pyridinium chloride and α- or ß-halo-containing sulfamides, chloroacetic acid, 1-chloro-2,3-dihydroxypropane, etc. The optimal conditions for the synchronous reaction of heterocyclization are determined. Benzenesulfonyliminopyridinium chloride was obtained to form pyrazolopyridines with 1,2-polarophiles, and pyridazine pyridines with 1,3-polarophiles. These novel derivatives were found as effective inhibitors of the α-glycosidase with Ki values in the range of 13.66 ± 2.63-60.63 ± 12.71 nM. The molecules (II-X) against enzyme were compared theoretically with the help of molecular docking to compare biological activities. The results were compared with the numerical values of the parameters obtained from molecular docking calculations and found to be in great agreement with the experimental results. However, ADME analysis of molecules was performed. Also, the compounds exhibited significant anticancer effect depending on the doses administered.Communicated by Ramaswamy H. Sarma.

Chemopreventive effect of riboflavin on the potassium bromate-induced renal toxicity in vivo.

Potassium bromate (PB) is a general food additive, flavor enhancer, a by-product of water disinfection, and a class 2 carcinogen. It exerts various toxic effects in a dose- and time-dependent manner in vivo. This study is to explore the chemopreventive efficacy of vitamin B2 (riboflavin, RF) in PB-administered Swiss albino rats. The rats were distributed into five groups: control (group 1), PB alone (group 2, 150 mg/kg), RF alone (group 3, 2 mg/kg), PB + RF1 (group 4, 150 and 2 mg/kg), and PB + RF2 (group 5, 150 and 4 mg/kg). All the rodents were sacrificed after the completion of the treatment cycle. Then, blood and kidney samples were subjected to biochemical analysis. Group 2 demonstrated vivid signs of renal toxicities evidenced by altered renal function markers (urea, creatinine, albumin, glutathione-S-transferase) and redox status parameters (superoxide dismutase, catalase, glutathione reductase, reduced glutathione, lipid, and protein oxidation products). However, group 3 exhibited a slight alteration in many of the parameters while groups 4 and 5 demonstrated dose-dependent chemopreventive efficiency of RF against PB-induced alterations. Besides, RF seemed to facilitate apoptosis as well as inhibition of the necrosis in the PB-pre-challenged groups, as demonstrated by the cleaved PARP and lactate dehydrogenase activity. Also, the histopathological analysis and comet assay validate the biochemical results of the treatment groups significantly. All these results plead that RF has a significant chemopreventive property against PB-induced toxicity in vivo. Therefore, RF is a suitable agent in preventing the PB-induced toxicities at the clinical and industrial levels.

A Switch between Antioxidant and Prooxidant Properties of the Phenolic Compounds Myricetin, Morin, 3',4'-Dihydroxyflavone, Taxifolin and 4-Hydroxy-Coumarin in the Presence of Copper(II) Ions: A Spectroscopic, Absorption Titration and DNA Damage Study.

The beneficial effects of polyphenols, predominantly in the context of oxidative stress-related diseases such as cancer, cardiovascular diseases and neurological conditions including Alzheimer's and Parkinson's diseases, have been documented by a number of papers and reviews. The antioxidant/prooxidant properties of phenolic compounds are related mainly to the number and positions of hydroxyl groups and to their redox metal (Cu, Fe) chelating capacity. In this work we studied structurally distinct phenolic molecules such as myricetin, morin, 3',4'-dihydroxy-flavone, taxifolin and 4-hydroxycoumarin, either alone or as interacting with Cu2+ ions. EPR and UV-Vis spectroscopy confirmed that the effective binding of cupric ions to phenolic compounds requires the presence of the 3-OH and 4-CO groups on the flavonoid C ring and unsaturated C2-C3 bond of the C-ring, which permits through-conjugation with the B-ring. An ABTS assay revealed that radical scavenging activities of phenolic compounds are related to their number of hydroxyl groups, planarity of the molecular skeleton, extent of delocalization and they decrease in the order: myricetin > morin > 3',4'-dihydroxyflavone ~ 4-hydroxy coumarin > taxifolin. Absorption titrations indicate that copper ions can modulate the DNA binding affinity of flavonoids via the formation of their Cu-chelates. Gel electrophoresis measurements indicated that the protective effect of the phenolic compounds decreases in the order: 3',4'-dihydroxyflavone > 4-OH coumarin > morin > taxifolin ~ myricetin. This can be explained by the fact that myricetin, taxifolin and morin form stable Cu(II) complexes capable of causing DNA damage via interaction with DNA and ROS formation via the Fenton reaction. Application of ROS scavengers revealed the formation of singlet oxygen, superoxide and hydroxyl radicals and their concerted synergistic effect on the DNA. The overall results suggest that the most pronounced DNA damage has been observed for flavonoids containing higher number of hydroxyl groups (including 3-OH group of the C ring), such as myricetin (six hydroxyl groups), morin and taxifolin (five hydroxyl groups) in the presence of Cu(II) ions. The proposed mechanism of action by which Cu(II) complexes of myricetin, morin and taxifolin interact with DNA predispose these substances to act as potential anticancer agents. The anticancer activity of phenolic compounds can be explained by their moderate prooxidant properties, which can boost ROS formation and kill cancer cells. Alternatively, slight prooxidant properties may activate antioxidant systems, including antioxidant enzymes and low molecular antioxidants such as glutathione and thus act as preventive anticancer agents.