Nickel oxide nanoparticles exert selective toxicity on skin mitochondria and lysosomes isolated from the mouse model of melanoma

Nickel oxide nanoparticles (NiO‐NPs) are progressively used for an immense number of new applications in modern industries sectors. Nevertheless, the toxic impact of NiO‐NPs has not been clearly elucidated on human melanoma cell lines at the cellular and molecular level. Hence, this study was designed to examine the in vitro cytotoxicity potentials of NiO‐NPs on malignant cutaneous melanoma (MCM) mitochondria. Results revealed that NiO‐NPs significantly increased reactive oxygen species level, lipid peroxidation, and mitochondrial membrane potential and decreased succinate dehydrogenase activity, glutathione level, and ATP content on skin mitochondria isolated from the mouse model of melanoma compared with the non‐cancerous mouse skin mitochondria. Our results revealed that NiO‐NPs induced lysosomal membrane labialization on mentioned mitochondria. The current study showed that NiO‐NPs could significantly induce selective cytotoxicity on MCM mitochondria. Therefore, this compound may be considered as a promising candidate for further in vivo and clinical studies to reach a new anti‐MCM drug.     

Air quality modeling for health risk assessment of ambient PM10, PM2.5 and SO2 in Iran

In this study, we have estimated the number of total mortality (T-mortality), cardiovascular morbidity (CV-mortality), respiratory mortality (R-mortality), hospital admissions due to cardiovascular diseases (HA-CVD), respiratory diseases (HA-RD), chronic obstructive pulmonary diseases (COPD) and acute myocardial infarction (AMI) due to exposure to particulate matter less than 10 µm (PM₁₀), 2.5 µm (PM_2.5) and sulfur dioxide (SO₂) in western Iran in 2016. The World Health Organization (WHO) method was used to assess the mortality and morbidity among the exposed people. The results showed that about 3.9% CM (95% CI: 2.9–7.8%), 3.9% HA-RD (95% CI: 2.4–7.8%) and 4.4% HA-CVD (95% CI: 3.0–6.8%) for ambient PM₁₀ and about 7.3% TM (95% CI: 4.2–9.7%), 12.1% CM (95% CI: 3.5–14.6%) and 3.0% RM (95% CI: 0–6.3%) for PM_2.5 are respectively attributed to concentrations exceeding 10 µg/m³. Furthermore, 3.2% HA-COPD (95% CI: 0–5.04%) and 4.2% AMI (95% CI: 1.6–4.3%) can be attributed to SO₂ concentrations greater than 10 µg/m³, respectively. To reduce the adverse health effect of PM, health advices provided by health authorities should be given to general population especially vulnerable people such as people with chronic lung and heart pathologies, elderly and children during the dusty days.     

Phenolics Impart Au3+-Stress Tolerance to Cowpea by Generating Nanoparticles

While evaluating impact of Au nanoparticles on seed germination and early seedling growth of cowpea, HAuCl₄ was used as control. Seedlings of cowpea raised in HAuCl₄, even at concentration as high as 1 mM, did not show any suppression in growth. Accordingly, Au³⁺, despite being a heavy metal, did not alter levels of stress markers (viz. proline and malondialdehyde) in cowpea. Interestingly, cowpea turned clear pale yellow HAuCl₄ solutions colloidal purple during the course of seed germination and seedling growth. These purple colloidal suspensions showed Au-nanoparticle specific surface plasmon resonance band in absorption spectra. Transmission electron microscopic and powder X-ray diffraction investigations confirmed presence of crystalline Au-nanoparticles in these purple suspensions. Each germinating seed of cowpea released ∼35 nmoles of GAE of phenolics and since phenolics promote generation of Au-nanoparticles, which are less/non toxic compared to Au³⁺, it was contemplated that potential of cowpea to withstand Au³⁺ is linked to phenolics. Of the different components of germinating seed of cowpea tested, seed coat possessed immense power to generate Au-nanoparticles, as it was the key source of phenolics. To establish role of phenolics in generation of Au-nanoparticles (i) seed coat and (ii) the incubation medium in which phenolics were released by germinating seeds, were tested for their efficacy to generate Au-nanoparticles. Interestingly, incubation of either of these components with Au³⁺ triggered increase in generation of Au-nanoparticles with concomitant decrease in phenolics. Accordingly, with increase in concentration of Au³⁺, a proportionate increase in generation of Au-nanoparticles and decrease in phenolics was recorded. In summary, our findings clearly established that cowpea possessed potential to withstand Au³⁺-stress as the phenolics released by seed coat of germinating seeds possess potential to reduce toxic Au³⁺ to form non/less toxic Au-nanoparticles. Our investigations also pave a novel, simple, green and economically viable protocol for generation of Au-nanoparticles.     

Targeting the microRNA binding domain of argonaute 2: rational inhibitor design and study of mutation effects on protein-ligand interaction

Abstract

Based on the accumulative evidences during recent decades, miRNAs have been found overexpressed in several human cancer types and also in Down syndrome patients, contributing to the neuropathology of Down syndrome. From this point of view, investigations on the structure and dynamic mechanisms related to the Argonaute 2 miRNAs binding in which silencing of the mRNA occurs, have inspired many clinical researchers to target this complex to inhibit the silencing process. In the current research, we have virtually screened the OTAVA_CNS_library to introduce new inhibitor compounds for the Ago2/miRNA complex. Ten hit compounds were obtained, with just one of them nominated as the best compound. Following the interaction analysis, by utilizing molecular dynamics (MD) simulations, effects of two mutations (Thr526 to isoleucine and Gln545 to alanine) on the dynamic properties of Ago2 in the complex with the best inhibitor compound were investigated. RMSD, RMSF and h-bond number beside other analyses, highlighted the importance of the Thr526 and Gln545 mutations for the stability and flexibility of the (Ago2)/ligand complex.

Communicated by Ramaswamy H. Sarma     

Generation of new human embryonic stem cell lines with diploid and triploid karyotypes

Human pluripotent embryonic stem cells (hESC) have great promise for research into human developmental biology and the development of cell therapies for the treatment of diseases. To meet the increased demand for characterized hESC lines, we present the derivation and characterization of five hESC lines on mouse embryonic fibroblast cells. Our stem cell lines are characterized by morphology, long-term expansion, and expression profiles of a number of specific markers, including TRA-1-60, TRA-1-81, alkaline phosphatase, connexin 43, OCT-4, NANOG, CXCR4, NODAL, LEFTY2, THY-1, TDGF1, PAX6, FOXD3, SOX2, EPHA2, FGF4, TAL1, AC133 and REX-1. The pluripotency of the cell line was confirmed by spontaneous differentiation under in vitro conditions. Whereas all of the cell lines expressed all the characteristics of undifferentiated pluripotent hESC, two of the cell lines carried a triploid karyotype.     

FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors

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Nitric oxide generation from heme/copper assembly mediated nitrite reductase activity

Nitric oxide (NO) as a cellular signaling molecule and vasodilator regulates a range of physiological and pathological processes. Nitrite (NO₂ ^?) is recycled in vivo to generate nitric oxide, particularly in physiologic hypoxia and ischemia. The cytochrome c oxidase binuclear heme a ₃/Cu_B active site is one entity known to be responsible for conversion of cellular nitrite to nitric oxide. We recently reported that a partially reduced heme/copper assembly reduces nitrite ion, producing nitric oxide; the heme serves as the reductant and the cupric ion provides a Lewis acid interaction with nitrite, facilitating nitrite (N–O) bond cleavage (Hematian et al., J. Am. Chem. Soc. 134:18912–18915, 2012). To further investigate this nitrite reductase chemistry, copper(II)–nitrito complexes with tridentate and tetradentate ligands were used in this study, where either O,O′-bidentate or O-unidentate modes of nitrite binding to the cupric center are present. To study the role of the reducing ability of the ferrous heme center, two different tetraarylporphyrinate–iron(II) complexes, one with electron-donating para-methoxy peripheral substituents and the other with electron-withdrawing 2,6-difluorophenyl substituents, were used. The results show that differing modes of nitrite coordination to the copper(II) ion lead to differing kinetic behavior. Here, also, the ferrous heme is in all cases the source of the reducing equivalent required to convert nitrite to nitric oxide, but the reduction ability of the heme center does not play a key role in the observed overall reaction rate. On the basis of our observations, reaction mechanisms are proposed and discussed in terms of heme/copper heterobinuclear structures.     

DEN+2-AAF-induced multistep hepatotumorigenesis in Wistar rats: supportive evidence and insights

Diethylnitrosamine (DEN), found in many commonly consumed foods, has been reported to induce cancers in animals and humans. Several models have been developed to study multistage carcinogenesis in rat liver; these include the Solt–Farber-resistant hepatocyte model. In the Solt–Farber model, the initiation consists of either a necrogenic dose of a hepatocarcinogen or a non-necrogenic dose in conjunction with partial hepatectomy (PH). We report a novel protocol for tumor induction in liver which eliminates the need for PH. Male Wistar rats were injected with single i.p. dose of DEN (200 mg/kg body weight), controls received saline only. After 1 week of recovery, the DEN-treated animals were administered with the repeated doses of 2-acetyamino fluorine (150 mg/kg body weight) orally in 1 % carboxymethyl cellulose that served as promoting agent. Thirty days after the DEN administration, hepatocellular damage was observed as evident by histopathological analysis. The marker enzyme analysis showed elevated levels of serum AST, ALT, and alkaline phosphatase and a decrease in the levels of liver superoxide dismutase and catalase. The oxidative stress in liver was confirmed by elevated levels of lipid peroxidation and a decrease in antioxidant parameters.     

High Level Activity of Recombinant Lysostaphin After Computer Simulation and Additive-Based Refolding

International Journal of Peptide Research and Therapeutics - Lysostaphin is a peptidoglycan hydrolase, produced by Staphylococcus simulans, which has illustrated significant bactericidal activities...     

Outcomes of deliveries by family physicians or obstetricians: a population-based cohort study using an instrumental variable

Background:

Previous research has suggested that obstetric outcomes are similar for deliveries by family physicians and obstetricians, but many of these studies were small, and none of them adjusted for unmeasured selection bias. We compared obstetric outcomes between these provider types using an econometric method designed to adjust for unobserved confounding.

Methods:

We performed a retrospective population-based cohort study of all Canadian (except Quebec) hospital births with delivery by family physicians and obstetricians at more than 20 weeks gestational age, with birth weight greater than 500 g, between Apr. 1, 2006, and Mar. 31, 2009. The primary outcomes were the relative risks of in-hospital perinatal death and a composite of maternal mortality and major morbidity assessed with multivariable logistic regression and instrumental variable–adjusted multivariable regression.

Results:

After exclusions, there were 3600 perinatal deaths and 14 394 cases of maternal morbidity among 799 823 infants and 793 053 mothers at 390 hospitals. For deliveries by family physicians v. obstetricians, the relative risk of perinatal mortality was 0.98 (95% confidence interval [CI] 0.85–1.14) and of maternal morbidity was 0.81 (95% CI 0.70–0.94) according to logistic regression. The respective relative risks were 0.97 (95% CI 0.58–1.64) and 1.13 (95% CI 0.65–1.95) according to instrumental variable methods.

Interpretation:

After adjusting for both observed and unobserved confounders, we found a similar risk of perinatal mortality and adverse maternal outcome for obstetric deliveries by family physicians and obstetricians. Whether there are differences between these groups for other outcomes remains to be seen.Over the past several decades in Canada, obstetric deliveries have increasingly been attended by specialist obstetricians rather than family physicians.¹ Although specialized care is beneficial for high-risk mothers and their infants,^2–4 there are concerns that it might increase risk for women whose deliveries could be safely managed without a specialized approach. Most prior studies have concluded that obstetric outcomes between family physicians and obstetricians are similar, but many of these studies were small, and none of them adjusted for unmeasured factors that might affect both the choice of delivery provider and outcomes.^5–8Obstetric risk is typically divided between providers, with family physicians and obstetricians sharing the lowest-risk patients, obstetricians caring for moderate-risk patients, and sub-specialized perinatologists caring for the highest-risk individuals. Although traditional statistical methods can be used to adjust for observed differences between these groups, they cannot be used to adjust for unobserved differences. For example, the presence of gestational diabetes mellitus is usually noted, but its severity is often not coded in administrative databases. Women with mild diabetes mellitus are usually eligible for delivery by family physicians, but those with severe diabetes (and the attendant increased risk of adverse outcome) are not. There are many prominent examples where traditional analyses of observational data produced results that were subsequently refuted by randomized trials, presumably because of these unmeasured or unknown factors that also affect treatment decisions or outcomes.^4,9–11The instrumental variable method from the field of econometrics is a technique designed to control for unmeasured covariates in regression analyses. Results from instrumental variable–controlled observational analyses of the effect of angiography after myocardial infarction⁹ and of long-acting bronchodilators on asthma control¹² closely approximated those of randomized controlled trials, whereas analyses using traditional statistical methods differed substantially. Instrumental variable analyses of obstetric data have shown that traditional statistical approaches significantly underestimate the mortality benefit of high-volume hospitals for high-risk neonates.⁴ The objective of the current study was to compare perinatal mortality and maternal morbidity and mortality for deliveries by family physicians and obstetricians using instrumental variable methodology.