Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: 1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; 2) the biological effect was influenced by the nature of the central azole ring of the ligands—1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; 3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin’s lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

NXP032 Ameliorates Aging-Induced Oxidative Stress and Cognitive Impairment in Mice through Activation of Nrf2 Signaling

Aging is a neurodegenerative disease that leads to cognitive impairment, and an increase in oxidative stress as a major cause is an important factor. It has been reported that aging-related cognitive impairment is associated with increased oxidative damage in several brain regions during aging. As a powerful antioxidant, vitamin C plays an important role in preventing oxidative stress, but due to its unstable chemical properties, it is easily oxidized and thus the activity of antioxidants is reduced. In order to overcome this easily oxidized vulnerability, we developed NXP032 (vitamin C/DNA aptamer complex) that can enhance the antioxidant efficacy of vitamin C using an aptamer. We developed NXP032 (vitamin C/DNA Aptamin C320 complex) that can enhance the antioxidant efficacy of vitamin C using an aptamer. In the present study, we evaluated the neuroprotective effects of NXP032 on aging-induced cognitive decline, oxidative stress, and neuronal damage in 17-month-old female mice. NXP032 was orally administered at 200 mg/kg of ascorbic acid and 4 mg/kg of DNA aptamer daily for eight weeks. Before the sacrifice, a cognitive behavioral test was performed. Administration of NXP032 alleviated cognitive impairment, neuronal damage, microglia activity, and oxidative stress due to aging. We found that although aging decreases the Nrf2-ARE pathway, NXP032 administration activates the Nrf2-ARE pathway to increase the expression of SOD-1 and GSTO1/2. The results suggest that the new aptamer complex NXP032 may be a therapeutic intervention to alleviate aging-induced cognitive impairment and oxidative stress.

Study of Antioxidants Vitamin E and Ascorbic Acid level in Pre-eclampsia and Normotensive Pregnant Women Attending the Antenatal Department of a Rural Hospital in Imo State South East Nigeria

Background: Deficiencies of nutrition are common during pregnancy especially in developing countries. Pregnant women in developing countries have been reported to consume diets that are low in minerals and vitamins. Inadequate dietary intake during pregnancy might be a high risk not only for the mother but also for the fetus. Deficiencies of antioxidant vitamins have been implicated in various reproductive disorders like infertility, congenital anomalies, pre-eclampsia, placental abruption, premature rupture of membranes, still births and low birth weight. Objective/Aim: This investigation was performed to compare the level of serum antioxidant vitamin E and Ascorbic Acid status in women with preeclampsia and normal pregnancy in Imo State. It was a randomized cross sectional study of 50 preeclampsia and 50 normotensive pregnant women attending the Dept. of Medicine and Antenatal clinic of specialist Hospital Umuguma, Owerri Imo State Nigeria. The study protocol was reviewed and the ethical committee and participants gave their consent. Data analysis was done using the statistical package for social sciences (SPSS) version 20.0. P-value of < 0.05 was considered to be statistically significant. Results: The mean antioxidant vitamins E and C were significantly lower in the preeclampsia group (0.29±0.07 and 0.31±0.20mg/dl) against the control (0.64±0.16 and 0.89±0.27mg/dl) P<0.05 respectively. Conclusion: The study showed significant decrease in the level of vitamin E and Ascorbic Acid suggesting the failure of compensatory antioxidant functions in preeclampsia women.

Comparative retrieval analysis of antioxidant polyethylene: bonding of vitamin-E does not reduce in-vivo surface damage

Background With the Persona® knee system a new polyethylene formulation incorporating vitamin-E which aims to reduce oxidation and maintain wear resistance was introduced. Although in-vitro studies have demonstrated positive effects of the vitamin-E antioxidants on UHMWPE, no retrieval study has looked at polyethylene damage of this system yet. It was the aim to investigate the in-vivo performance of this new design, by comparing it with its predecessor in retrieval analysis. Methods 15 NexGen® and 8 Persona® fixed-bearing implants from the same manufacturer (Zimmer Biomet) were retrieved from two knee revision centres. For retrieval analysis, a macroscopic analysis of polyethylene using a peer-reviewed damage grading method was used (Hood-score). The roughness of all articulating metal components was measured using a contact profilometer. The reason(s) for TKA revision were recorded. Statistical analyses (t-test) were performed to investigate differences between the two designs. Results The mean Hood score for Persona® inserts was 109.3 and for NexGen® 115.1 without significant differences between the two designs. Results from the profilometer revealed that Persona® and NexGen® femoral implants showed an identical mean surface roughness of 0.14 μm. The Persona® tibial tray showed a significantly smoother surface (0.06 μm) compared to the NexGen® (0.2 μm; p < 0.001). Both Hood score and surface roughness were influenced by the reasons for revision (p < 0.01). Conclusions The bonding of the antioxidant vitamin-E to the PE chain used in the novel Persona® knee system does not reduce in-vivo surface damage compared to highly crosslinked PE without supplemented vitamin-E used in its predecessor knee system NexGen®. However, the Persona® titanium alloy tibial tray showed a significantly smoother surface in comparison to the NexGen® titanium alloy tibial tray. This study provides first retrieval findings of a novel TKA design and may help to understand how the new Persona® anatomic knee system performs in vivo.

In vitro antioxidant activity and phytochemical analyses of Acalypha godseffiana (Euphobiaceae) leaf extracts

The presence of various bioactive components makes it necessary to analyse plants for their potential to act as a source of useful treatments and cures for many inflammatory, infectious and pathogenic diseases. This study was carried out to determine phytochemicals and in-vitro antioxidant activities of the leaf extracts of Acalypha godseffiana. The leaves of A. godseffiana were collected, dried, pulverized and extracted separately with methanol and water using maceration method. The extract was concentrated in vacuo with rotary evaporator at 40oC. The extracts were subjected to quantitative phytochemical analysis and different anti-oxidant analytical procedures like FRAP, DPPH etc to determine the radical scavenging capabilities. The results of phytochemical analysis estimated the quantities and revealed the presence of alkaloids, flavonoids, tannins, saponins and terpenoids which varied in both extracts. The methanol and aqueous extracts exhibited antioxidant activities with relatively high IC50 (IC50 = 3.67 ìg/ml and 4.42ìg/ml respectively) which accounted for a low free radical-scavenging activity when compared with the reference antioxidant, vitamin C (IC50 = 1.51ìg/ml). The results of the study indicates that A. godseffiana leaf extracts contain secondary metabolites and possesses antioxidant properties.

Negative Influence of Insufficient Sleep on Endothelial Vasodilator and Fibrinolytic Function in Hypertensive Adults

Insufficient nightly sleep (<7 hour/night) has been linked to the cause of hypertension and is a prevalent, often ignored, comorbidity. We tested the hypotheses that chronic nightly insufficient sleep is associated with lower nitric oxide-mediated endothelium-dependent vasodilation and endothelial tPA (tissue-type plasminogen activator) release in hypertensive adults; and that the insufficient sleep-related reduction in endothelial vasodilator and fibrinolytic function is due to increased oxidative stress. Fifty hypertensive adults were studied: 20 with normal nightly sleep duration (14M/6F; age: 59±2 year; blood pressure: 138/83±1/1 mm Hg; sleep: 7.6±0.1 hour/night) and 30 with short nightly sleep duration (21M/9F; 56±1 year; 138/84±2/1 mm Hg; 5.8±0.1 hour/night). Forearm blood flow (plethysmography) was determined in response to intraarterial infusion of: acetylcholine in the absence and presence of N G -monomethyl-L-arginine and the antioxidant vitamin C; bradykinin in the absence and presence of vitamin C; and sodium nitroprusside. Endothelial release of tPA was determined in response to bradykinin without and with vitamin C. Vasodilation to acetylcholine was significantly lower (≈20%) in the short versus normal sleep adults. N G -monomethyl-L-arginine reduced (≈25%; P <0.05) acetylcholine vasodilation in the normal but not short sleepers. Vitamin C increased (≈35%; P <0.05) acetylcholine vasodilation in short sleepers only. Endothelial tPA release to bradykinin was significantly lower (≈25%) in the short versus normal sleep duration adults. Co-infusion of vitamin C induced greater tPA release in short sleepers. In hypertensive adults, insufficient sleep is associated with reduced nitric oxide–mediated endothelium-dependent vasodilation and endothelial tPA release. These sleep-related abnormalities in endothelial function are due, in part, to oxidative stress.

Impact of Amyloid-β on Platelet Mitochondrial Function and Platelet–Mediated Amyloid Aggregation in Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is characterized by an accumulation of amyloid β (Aβ) peptides in the brain and mitochondrial dysfunction. Platelet activation is enhanced in AD and platelets contribute to AD pathology by their ability to facilitate soluble Aβ to form Aβ aggregates. Thus, anti-platelet therapy reduces the formation of cerebral amyloid angiopathy in AD transgenic mice. Platelet mitochondrial dysfunction plays a regulatory role in thrombotic response, but its significance in AD is unknown and explored herein. Methods: The effects of Aβ-mediated mitochondrial dysfunction in platelets were investigated in vitro. Results: Aβ40 stimulation of human platelets led to elevated reactive oxygen species (ROS) and superoxide production, while reduced mitochondrial membrane potential and oxygen consumption rate. Enhanced mitochondrial dysfunction triggered platelet-mediated Aβ40 aggregate formation through GPVI-mediated ROS production, leading to enhanced integrin αIIbβ3 activation during synergistic stimulation from ADP and Aβ40. Aβ40 aggregate formation of human and murine (APP23) platelets were comparable to controls and could be reduced by the antioxidant vitamin C. Conclusions: Mitochondrial dysfunction contributes to platelet-mediated Aβ aggregate formation and might be a promising target to limit platelet activation exaggerated pathological manifestations in AD.

Mechanisms Underlying the Protective Effect of the Peroxire-Doxin-6 Are Mediated via the Protection of Astrocytes during Ischemia/Reoxygenation

Ischemia-like conditions reflect almost the entire spectrum of events that occur during cerebral ischemia, including the induction of oxidative stress, Ca2+ overload, glutamate excitotoxicity, and activation of necrosis and apoptosis in brain cells. Mechanisms for the protective effects of the antioxidant enzyme peroxiredoxin-6 (Prx-6) on hippocampal cells during oxygen-glucose deprivation/reoxygenation (OGD/R) were investigated. Using the methods of fluorescence microscopy, inhibitory analysis, vitality tests and PCR, it was shown that 24-h incubation of mixed hippocampal cell cultures with Prx-6 does not affect the generation of a reversible phase of a OGD-induced rise in Ca2+ ions in cytosol ([Ca2+]i), but inhibits a global increase in [Ca2+]i in astrocytes completely and in neurons by 70%. In addition, after 40 min of OGD, cell necrosis is suppressed, especially in the astrocyte population. This effect is associated with the complex action of Prx-6 on neuroglial networks. As an antioxidant, Prx-6 has a more pronounced and astrocyte-directed effect, compared to the exogenous antioxidant vitamin E (Vit E). Prx-6 inhibits ROS production in mitochondria by increasing the antioxidant capacity of cells and altering the expression of genes encoding redox status proteins. Due to the close bond between [Ca2+]i and intracellular ROS, this effect of Prx-6 is one of its protective mechanisms. Moreover, Prx-6 effectively suppresses not only necrosis, but also apoptosis during OGD and reoxygenation. Incubation with Prx-6 leads to activation of the basic expression of genes encoding protective kinases—PI3K, CaMKII, PKC, anti-apoptotic proteins—Stat3 and Bcl-2, while inhibiting the expression of signaling kinases and factors involved in apoptosis activation—Ikk, Src, NF-κb, Caspase-3, p53, Fas, etc. This effect on the basic expression of the genome leads to the cell preconditions, which is expressed in the inhibition of caspase-3 during OGD/reoxygenation. A significant effect of Prx-6 is directed on suppression of the level of pro-inflammatory cytokine IL-1β and factor TNFα, as well as genes encoding NMDA- and kainate receptor subunits, which was established for the first time for this antioxidant enzyme. The protective effect of Prx-6 is due to its antioxidant properties, since mutant Prx-6 (mutPrx-6, Prx6-C47S) leads to polar opposite effects, contributing to oxidative stress, activation of apoptosis and cell death through receptor action on TLR4.

Total Phenolic Content, Antioxidant and Antibacterial Activities of Sargassum polycystum of Ethanol Extract from Waters of Kabung Island

Sargassum policystum is one of the genus Sargassum from the brown macroalgae group which has an abundance of chemical constituents of fucoidan, fucoxanthin, phenolic acids and alginate which have important biological activities, such as antioxidants and antibacterials. This species thrives in the waters of Kabung Island, Bengkayang, West Kalimantan and has not been exploited so that it tends to act as a marine weed. This study aimed to determine the total phenolic content of the ethanolic extract of S. policystum and its antioxidant and antibacterial activity. Determination of the total content of phenolic compounds using the Folin Ciocalteu method, antioxidant testing using the DPPH method (2,2-diphenyl-1-picrylhydrazyl) and the indicator of sample color change with the addition of these radicals was measured by UV-Vis spectrophotometer. Antibacterial testing was carried out by the test sample diffusion method and the inhibition of the growth of the test bacteria Staphylococcus aureus and Escherichia coli as test bacteria was indicated by the formation of a clear area around the sample wells. The results showed that the phenol content of the ethanolic extract of S. policystum was 79.8 mg/g extract, its antioxidant activity (IC50) was 98.903 ppm, classified as a strong antioxidant, while the comparison antioxidant, Vitamin C, had an IC50 of 6.26 ppm. The inhibitory ability of the ethanol extract against the test bacteria used was indicated by the formation of the largest inhibition diameter on S. aureus of 12.4 mm and E. coli of 12.0 mm.