Mitigating Agents Research Articles

Oxidative Stress, Oxidative Damage, and Cell Apoptosis: Toxicity Induced by Arecoline in Caenorhabditis elegans and Screening of Mitigating Agents.

As the areca nut market is expanding, there is a growing concern regarding areca nut toxicity. Areca nut alkaloids are the major risky components in betel nuts, and their toxic effects are not fully understood. Here, we investigated the parental and transgenerational toxicity of varied doses of areca nut alkaloids in Caenorhabditis elegans. The results showed that the minimal effective concentration of arecoline is 0.2-0.4 mM. First, arecoline exhibited transgenerational toxicity on the worms' longevity, oviposition, and reproduction. Second, the redox homeostasis of C. elegans was markedly altered under exposure to 0.2-0.4 mM arecoline. The mitochondrial membrane potential was thereafter impaired, which was also associated with the induction of apoptosis. Moreover, antioxidant treatments such as lycopene could significantly ameliorate the toxic effects caused by arecoline. In conclusion, arecoline enhances the ROS levels, inducing neurotoxicity, developmental toxicity, and reproductive toxicity in C. elegans through dysregulated oxidative stress, cell apoptosis, and DNA damage-related gene expression. Therefore, the drug-induced production of reactive oxygen species (ROS) may be crucial for its toxic effects, which could be mitigated by antioxidants.

Predictability of the Spatiotemporal Pattern of Wild Boar (Sus scrofa) Rooting Influenced by Acorn Availability

The natural regeneration of the temperate oak forests is often insufficient. Acorns of the oak serve as the basis of the recruitment and key food resources in these ecosystems, thus the crop size, the germination success and seed predators have crucial roles in the process. Wild boar (Sus scrofa) is often considered as one of the main mitigating agents in oak regeneration. Therefore, in our study we analyzed and compared the spatial patterns of the acorn density and the patches rooted by wild boar within and among the different examined time intervals in a 28 ha Turkey-sessile oak (Quercus cerris, Q. petraea) forest stand. Data were collected between 2016 October and 2019 December. In the acorn density patterns, intra-annual similarities were recognized mainly, regardless of the crop size. Meanwhile, rooting patterns showed inter- and intra-annual similarities in mast years and intra-annual overlaps in non-mast years, indicating that masting is a fundamental driver of wild boar foraging behavior. However, a direct local connection between the rooting intensity and the acorn density could not be shown, as wild boars never fully depleted the acorns, even in intensively used patches. This study can help in predicting the intensively rooted forest patches, providing opportunities to manage wildlife conflicts.

A Review on The Biological, Physical and Chemical Mitigation of Harmful Algal Bloom

The harmful algal bloom (HABs) refers to the rapid growth of toxic or high-biomass-producing microalgae. The impact of this phenomenon can cause significant economic loss affecting many industries and causing harm to wildlife and human health. As technology develops, greater research has been conducted to monitor and reduce HABs occurrence’s impact, including mitigating agents. This review presents the advantages and disadvantages of currently used and recently developed biological, chemical, and physical approaches to tackle issues related to HABs. The present review also emphasizes the interaction between the mitigating agents and the algal cells, thus identifying the gap of knowledge that needs to be addressed. Understanding the advantages and disadvantages of the approaches and the interaction between the mitigating agents and algal cells will enable researchers to develop a better sustainable system for managing HAB.

Nanoparticles for active combination radio mitigating agents of zinc coumarate and zinc caffeinate in a rat model.

Zinc coumarate and zinc caffeinate nanoparticles (ZnCoNPs, ZnCaNPs) affect different biological processes. This study aimed to evaluate the mitigating action of ZnCoNPs in combination with ZnCaNPs against liver damage induced by gamma rays (γ-rays). Rats were exposed to 7Gy of γ-rays and then injected intraperitoneally (i.p) with ZnCoNPs [2U/rat/day (5mg/kg)] and ZnCaNPs [2U/rat/day (15mg/kg)] for 7 consecutive days. The results showed that irradiated rats treated with ZnCoNPs (5mg/kg/body weight) in combination with ZnCaNPs (15mg/kg/body weight) for 7days had a significant increases in body weight, antioxidant levels, T helper cell 4 (cluster of differentiation 4 (CD4)), and T cytotoxic cell 8 (cluster of differentiation 8 (CD8)), associated with a marked decrease in lipid peroxidation (LP), nitric oxide(NOx), total free radicals concentrate (TFRC), and DNA fragmentation. There were positive alterations in the morphological state, hematological parameters and the cell cycle phases. Additionally, the histopathological study demonstrated an improvement in the liver tissue of irradiated rats after treatment. Thus, ZnCoNPs and ZnCaNPs could be used as natural mitigating agents to reduce the hazards of ionizing radiation.

Microbial Resources, Fermentation and Reduction of Negative Externalities in Food Systems: Patterns toward Sustainability and Resilience

One of the main targets of sustainable development is the reduction of environmental, social, and economic negative externalities associated with the production of foods and beverages. Those externalities occur at different stages of food chains, from the farm to the fork, with deleterious impacts to different extents. Increasing evidence testifies to the potential of microbial-based solutions and fermentative processes as mitigating strategies to reduce negative externalities in food systems. In several cases, innovative solutions might find in situ applications from the farm to the fork, including advances in food matrices by means of tailored fermentative processes. This viewpoint recalls the attention on microbial biotechnologies as a field of bioeconomy and of ‘green’ innovations to improve sustainability and resilience of agri-food systems alleviating environmental, economic, and social undesired externalities. We argue that food scientists could systematically consider the potential of microbes as ‘mitigating agents’ in all research and development activities dealing with fermentation and microbial-based biotechnologies in the agri-food sector. This aims to conciliate process and product innovations with a development respectful of future generations’ needs and with the aptitude of the systems to overcome global challenges.

Design of a Microfluidic Bleeding Chip to Evaluate Antithrombotic Agents for Use in COVID-19 Patients.

IntroductionInterventions that could prevent thrombosis, clinical decompensation, and respiratory compromise in patients with novel coronavirus disease (COVID-19) are key to decrease mortality rate. Studies show that profound cytokine release and excessive activation of blood coagulation appear to be key drivers of COVID-19 associated mortality. Since limited in vitro methods exist for assessing the effects of anticoagulants on hemostasis, the development of novel therapies to safely prevent thrombosis in COVID-19 patients relies on preclinical animal models and early phase human trials. Herein we present the design of a microfluidic “bleeding chip” to evaluate the effects of antithrombotic therapies on hemostatic plug formation in vitro.MethodsThe design of the microfluidic device consists of two orthogonal channels: an inlet that serves as a model blood vessel, and a bleeding channel to model hemostatic plug formation at sites of compromised endothelial barrier function. This is achieved by placing a series of 3 pillars spaced 10 μm apart at the intersection of the two channels. The pillars and bleeding channel are coated with the extracellular matrix protein collagen.ResultsPerfusion of human whole blood through the microfluidic bleeding chip led to initial platelet adhesion and aggregation at the pillars followed by hemostatic plug formation and occlusion of the bleeding channel.ConclusionsSafe and effective mitigating agents are needed for treatment and prevention of thrombotic complications in COVID-19 patients. This simple microfluidic device holds potential to be developed into a tool for assessing the effects of anticoagulant therapy on hemostasis.

INVESTIGATION OF THE RADIOPROTECTIVE EFFECT OF ORTHOVANADATE IN MICE AFTER TOTAL BODY IRRADIATION.

The increasing risk of acute large-scale exposure of ionising irradiation on the population underlines the necessity of developing effective radioprotective and mitigating agents. The aim of this work was to investigate the effect of sodium orthovanadate pre-treatment on mice exposed to high doses of gamma rays (from 5 to 13Gy). The determination of median lethal dose within 30days confirmed that orthovanadate applied to total-body-irradiated mice intra-peritoneally has a radioprotective but not a mitigating effect. With orthovanadate pre-treatment, the composition of cellularity in the bone marrow improved substantially and the main lymphocyte populations restored during the first month after irradiation. These findings contribute to 'gap-filling' in radioprotective effects and demonstrate the importance of haematological parameters in radiation-response prediction.

Effect of combining wheat grain with nitrate, fat or 3-nitrooxypropanol on in vitro methane production

Enteric methane emitted by ruminants is a nutritional inefficiency that contributes to global warming. Feeding substantial quantities of wheat grain to dairy cows has been reported to decrease enteric methane emissions compared with other feeds. Feeding methane mitigating agents such as nitrate, fat and 3-nitrooxypropanol (3-NOP) to ruminants have also been reported to decrease enteric methane emissions. This research involved three in vitro experiments that examined the combined effect of wheat grain with nitrate, fat or 3-NOP on in vitro methane mitigation. In each of the experiments, wheat grain or corn grain were incubated in combination with one of the three methane mitigating agents (nitrate, fat or 3-NOP). The fermentation of wheat grain produced 22% less methane than the fermentation of corn grain. All three methane mitigating agents decreased in vitro methane production and methane production expressed per gram of dry matter degraded. The addition of nitrate, fat and 3-NOP decreased in vitro methane production by 21, 19 and 44% respectively. The methane mitigating effect of wheat grain in combination with nitrate, fat or 3-NOP was greater than the individual effects of wheat grain, nitrate, fat or 3-NOP. The feeding of the combination of wheat grain with nitrate, fat or 3-NOP to ruminants may be effective strategies for decreasing their enteric methane emissions.

Post-stress bacterial cell death mediated by reactive oxygen species

Antimicrobial efficacy, which is central to many aspects of medicine, is being rapidly eroded by bacterial resistance. Since new resistance can be induced by antimicrobial action, highly lethal agents that rapidly reduce bacterial burden during infection should help restrict the emergence of resistance. To improve lethal activity, recent work has focused on toxic reactive oxygen species (ROS) as part of the bactericidal activity of diverse antimicrobials. We report that when Escherichia coli was subjected to antimicrobial stress and the stressor was subsequently removed, both ROS accumulation and cell death continued to occur. Blocking ROS accumulation by exogenous mitigating agents slowed or inhibited poststressor death. Similar results were obtained with a temperature-sensitive mutational inhibition of DNA replication. Thus, bacteria exposed to lethal stressors may not die during treatment, as has long been thought; instead, death can occur after plating on drug-free agar due to poststress ROS-mediated toxicity. Examples are described in which (i) primary stress-mediated damage was insufficient to kill bacteria due to repair; (ii) ROS overcame repair (i.e., protection from anti-ROS agents was reduced by repair deficiencies); and (iii) killing was reduced by anti-oxidative stress genes acting before stress exposure. Enzymatic suppression of poststress ROS-mediated lethality by exogenous catalase supports a causal rather than a coincidental role for ROS in stress-mediated lethality, thereby countering challenges to ROS involvement in antimicrobial killing. We conclude that for a variety of stressors, lethal action derives, at least in part, from stimulation of a self-amplifying accumulation of ROS that overwhelms the repair of primary damage.

Bio-accumulation of lanthanum from lanthanum modified bentonite treatments in lake restoration

Lanthanum (La) modified bentonite (LMB) is one of the available mitigating agents used for the reduction of the phosphorus (P) recycling in eutrophic lakes. The potential toxicity of the La from LMB to aquatic organisms is a matter of concern. In this study the accumulation of La was investigated in the macrophyte Elodea nuttallii, in chironomid larvae and in several fish species during periods up to five years following in situ LMB applications. The application of LMB increased the La concentration of exposed plants and animals. During the first growing season following LMB applications, the La content of E. nuttallii increased 78 fold (3.98–310.68 μg La g−1 DW) to 127 fold (2.46–311.44 μg La g−1). During the second growing season following application, the La content decreased but was still raised compared to plants that had not been exposed. The La content of chironomids was doubled in the two years following LMB application, although the increase was not significant. Raised La concentrations in fish liver, bone, muscle and skin were observed two and five years following to LMB application. Liver tissues showed the highest La increase, ranging from 6 fold (0.046–0.285 μg La g−1 DW) to ∼20 fold (0.080–1.886 μg La g−1, and 0.122–2.109 μg La g−1) two years following application and from 6 fold (0.046–0.262 μg La g−1) to 13 fold (0.013–0.167 μg La g−1) after five years in pelagic and littoral fish. The La content of the liver from Anguilla anguilla (eel) had increased 94 fold (0.034–3.176 μg La g−1) two years and 133 fold (0.034–4.538 μg La g−1) five years following LMB application. No acute and chronic effects of La accumulation were observed and human health risks are considered negligible. We advocate the long-term study of effects of La accumulation following future LMB applications.

Cyber victimization and adjustment difficulties: The mediation of Chinese and American adolescents’ digital technology usage

Researchers have focused on identifying factors which might reduce the negative consequences associated with cyber victimization. One prominent factor receiving attention is the role of parental mediation in adolescents’ digital technology usage, and how such mediation reduces the risk of cyber victimization. Less attention has focused on different mitigating agents (i.e., teachers, friends) and their influence on adolescents’ cyber victimization. Another area that has received little attention is the buffering effects of different mitigating agents on the psychosocial adjustment difficulties (i.e., depression, loneliness, anxiety) associated with cyber victimization. To address this gap in the literature, the present study investigated the role of different mitigating agents (i.e., parents, teachers, friends) in buffering against the psychosocial adjustment difficulties associated with cyber victimization among 483 Chinese (49% female) and 467 American (52% female) adolescents in the eighth grade (ages ranging from 13-15). Findings revealed that all adolescents experienced more mediation by their parents, with Chinese adolescents reporting more parental mediation when compared to American adolescents. Chinese adolescents also reported more teacher mediation, while American adolescents experienced more friend mediation. In addition, high levels of parental mediation made the relationship of cyber victimization to depression and anxiety more negative for both Chinese and American adolescents. The relationships of cyber victimization to depression and anxiety were moderated by teacher mediation for Chinese adolescents, whereas this pattern was not found for American adolescents. On the other hand, friend mediation moderated the relationship of cyber victimization to depression and anxiety for American adolescents, but not for Chinese adolescents. The results of this study are discussed in terms of cultural values and how such values alter the role of adults and friends in adolescents’ lives.

Myocardial metabolism in diabetic cardiomyopathy: potential therapeutic targets.

Cardiovascular complications in diabetes are particularly serious and represent the primary cause of morbidity and mortality in diabetic patients. Despite early observations of cardiac dysfunction in diabetic humans, cardiomyopathy unique to diabetes has only recently been recognized. Research has focused on understanding the pathogenic mechanisms underlying the initiation and development of diabetic cardiomyopathy. Emerging data highlight the importance of altered mitochondrial function as a major contributor to cardiac dysfunction in diabetes. Mitochondrial dysfunction occurs by several mechanisms involving altered cardiac substrate metabolism, lipotoxicity, impaired cardiac insulin and glucose homeostasis, impaired cellular and mitochondrial calcium handling, oxidative stress, and mitochondrial uncoupling. Currently, treatment is not specifically tailored for diabetic patients with cardiac dysfunction. Given the multifactorial development and progression of diabetic cardiomyopathy, traditional treatments such as anti-diabetic agents, as well as cellular and mitochondrial fatty acid uptake inhibitors aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose may not adequately target all aspects of this condition. Thus, an alternative treatment such as resveratrol, which targets multiple facets of diabetes, may represent a safe and promising supplement to currently recommended clinical therapy and lifestyle changes. Elucidation of the mechanisms underlying the initiation and progression of diabetic cardiomyopathy is essential for development of effective and targeted treatment strategies. Of particular interest is the investigation of alternative therapies such as resveratrol, which can function as both preventative and mitigating agents in the management of diabetic cardiomyopathy.

Artesunate Induced Hepato-Toxicity and its Amelioration by Allium sativum in Swiss Albino Male Mice

The use of natural antioxidants as mitigating agents has become prevalent. Garlic (Allium sativum) is one such agent which has been proven to have antibacterial, antiseptic, antifungal, antiparasitic, anticoagulant and antitumor properties. The present investigation deals with the ameliorative effects of Allium sativum on the antimalarial drug induced hepato-toxicity. Artesunate is being used as an alternative anti-malarial drug against conventional drugs like chloroquine. Experimental animals were divided into six groups of six mice each. Group A served as the control group. Group B and Group C animals were given 150 mg/kg b.wt and 300 mg/kg b.wt of artesunate respectively while Group D mice were given 100 mg/kg b.wt of Allium sativum. Group E and F mice were given 150 mg/kg b.w of artesunate+100 mg/kg b.wt Allium sativum and 300 mg/kg b.wt of artesunate+100 mg/kg b.wt Allium sativum respectively. Results exhibited recovery and re-establishment of various altered indices as opposed to Artesunate treated groups. Thus, Allium sativum might be used as a potent mitigating agent against anti-malarial drug toxicity. However, further research is needed to completely elucidate the ameliorative efficacy of Allium sativum.

Mineralogical and chemical variations of ochreous precipitates from acid sulphate waters (asw) at the Roşia Montană gold mine (Romania)

The mineralogical and chemical variations of ochreous precipitates forming from acid sulphate waters discharged from the lowest mine adit (“Sf. Cruci din Orlea”) of the Rosia Montană Gold Mine (Romania) were investigated by a multianalytical approach (XRPD, IR, TEM, ICP) applied to surface precipitates and associated waters. The mineralogy of the precipitates changed significantly as a consequence of the variations in the chemical parameters of the circulating solutions (mainly pH, Eh, and sulphate concentrations) which were mainly controlled by mixing with unpolluted waters of Rosia River. Ochreous precipitates are characterized by high concentrations of potentially toxic elements (PTEs; in particular Cr, Co, Ni, Cu, Zn, As, Cd, and Pb) and consist of a mixture, in variable proportion, of jarosite and schwertmannite, which represent the stable secondary minerals along the investigated transect of Rosia River. Particular regard is given to the ability of authigenic phases to selectively scavenge selected PTEs from contaminated solutions during their genesis and minerogenetic evolution. Furthermore, laboratory kinetic batch experiments on natural heterogeneous samples of ochreous precipitates were carried out to investigate the release processes involving PTEs and to verify the type and the amount of elements that can be temporarily/permanently trapped by the solid phase from the contaminated solutions. The comparative analysis of the precipitates and waters of the Rosia Montană mining area indicated that the role of secondary minerals as “mitigating agents” can be limited because even minor pH–Eh oscillations would cause mineralogical transformations that could lead to trace elements mobilization in the environment.

Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis — A Literature Review

As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus) remains one of the best animal model systems for cancer research due to its molecular and physiological similarities to man, small size, ease of breeding in captivity and a fully sequenced genome. This work reviews relevant M. musculus inbred and F1 hybrid animal models and methodologies of induction of radiation-induced leukemia, thymic lymphoma, breast, and lung cancer in these models. Where available, the associated molecular pathologies are also included.

Contemporary Radiation Countermeasure

Radiation countermeasures have been investigated for decades, but the search for ideal protective agents for use prior to or after irradiation still continues. This review focuses on agents that have demonstrated as potential as in vivo countermeasure agents and may subsequently be effectively used in human beings. Such agents are categorised as radioprotectors, radiation mitigators, or therapeutic agents dependening upon their time of administration. These protective or mitigating agents are designed to reduce inadvertent damage to normal tissue caused by radiation. These interventions function via various mechanisms of action ranging from modulating signalling pathways to inhibiting cell death, cytokines, and growth factor. Many agents demonstrated promising results in murine models and are being tested in human beings. Amifostine, and curcumin have shown radioprotection, while genistein, palifermin, and halofuginone have been shown to alleviate the side effects in patients undergoing radiotherapy. Though these compounds show some promise as radiation countermeasure agents, there are several associated limitations and the search for perfect agents still continues.

Animal Models for Medical Countermeasures to Radiation Exposure

Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.

Predictors and correlates for weight changes in patients co-treated with olanzapine and weight mitigating agents; a post-hoc analysis.

BackgroundThis study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions.MethodsData were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) ≥ 25 kg/m2 who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss ≥ 2 kg and weight gain ≥ 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale.ResultsPredictors/correlates of weight loss ≥ 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain ≥ 1 kg.ConclusionThe association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy.Trial RegistrationThis analysis was not a clinical trial and did not involve any medical intervention.

Investigation of possible free-radical scavengers and metrics for radiation damage in protein cryocrystallography.

The introduction of highly intense wiggler and undulator beamlines has reintroduced the problem of X-ray radiation damage in protein crystals even at cryogenic temperatures. Several metrics for monitoring radiation damage are considered and unit-cell volume expansion is systematically investigated using crystals of three different types, but it is found to be too variable to be a useful metric. Radical scavengers of secondary radiation damage are investigated as possible mitigating agents. Styrene is found to be ineffective. A method of spectroscopically measuring the radiation damage with a microspectrophotometer was used and, in conjunction with crystallographic data, provided tentative but suggestive evidence for the efficacy of ascorbate as a free-radical scavenging agent in cryocooled hen egg-white lysozyme crystals.