Does acute exposure to thimerosal, an organic mercury compound, affect the mitochondrial function of an infant model?

BACKGROUND: Thimerosal (TM) is a toxic, organometallic mercury compound (which releases ethyl-mercury-containing compounds in aqueous solutions) used as a preservative in vaccines. Mitochondria are organelle which are highly vulnerable to many chemical compounds, including mercury (Hg) and its derivatives. METHOD: Wistar rats (at 21 days of age) were used to model a child's TM exposure following childhood vaccination, divided in two groups: TM exposed (20 µg/kg/day) and unexposed controls (saline solution), both for 24 h. Atomic Fluorescence Spectrometry was used to quantify the amounts of mercury in tissues. The electron transport chain (ETC) from isolated mitochondria was evaluated using an oxygen electrode. The mitochondrial membrane potential and H2O2 production were analyzed using selective fluorescence probes. The activity of some enzymes (SOD, CAT, GPx, and AChE) and secondary markers of oxidative stress (GSH, GSSG, total free thiol) were also examined in tissues. RESULTS: Hg accumulation in the brain and liver was higher in exposed animals when compared to the control. Liver-isolated mitochondria showed that TM improved respiratory control by 23%; however, states 3 and 4 of the ETC presented a decrease of 16% and 37%, respectively. Furthermore, brain-isolated mitochondria presented an improvement of 61% in respiratory control. Brain enzyme activities were significantly impacted in TM-exposed rats compared to unexposed rats as follows: decreases in SOD (32%) and AChE (42%) and increases in GPx (79%) and CAT (100%). GPx enzyme activity in the liver was significantly increased (37%). Among secondary oxidative stress markers, the brain's total reduced thiol (SH) concentration was significantly increased (41%). CONCLUSION: Acute TM treatment exposure in a Wistar rat model mimicking TM exposure in an infant following childhood vaccination significantly damaged brain bioenergetic pathways. This study supports the ability of TM exposure to preferentially damage the nervous system.

Synthesis of hydrazinyl-thiazole ester derivatives, in vitro trypanocidal and leishmanicidal activities.

Aim: To synthesize novel more potent trypanocidal and leishmanicidal agents. Methods: Hantzsch's synthetic strategy was used to synthesize 1,3-thiazole-4-carboxylates and their N-benzylated derivatives. Results: 28 new thiazole-carboxylates and their N-benzylated derivatives were established to test their trypanocidal and leishmanicidal activities. From both series, compounds 3b, 4f, 4g, 4j and 4n exhibited a better or comparable trypanocidal profile to benznidazole. Among all tested compounds, 4n was found to be the most potent and was better than benznidazole. Conclusion: Further variation of substituents around 1,3-thiazole-4-carboxylates and or hydrazinyl moiety may assist in establishing better and more potent trypanocidal and leishmanicidal agents.

Chagas disease and leishmaniasis are neglected tropical diseases. Herein, 28 1,3-thiazoles have been synthesized from thiosemicarbazones in a rapid, efficient and cost-effective manner. In vitro assays were performed against intracellular amastigotes of Trypanosoma cruzi (T. cruzi) and promastigotes and intracellular amastigote forms of Leishmania infantum (L. infantum) and Leishmania amazonensis (L. amazonensis). Some of the 1,3-thiazole-4-carboxylates inhibited the amastigote form of T. cruzi without affecting macrophage viability, compound 4n being the most potent and better than benznidazole. Our synthesized compounds exhibited promising activity against T. cruzi, thus broadening options for scaffold and lead compound optimization. Concerning the leishmanicidal activity, compound 4g was the best prototype in terms of potency and selectivity. Compounds 4g and 3m showed moderate selectivity and potency against intracellular amastigotes of L. amazonensis and L. infantum, respectively.

The impact of risk perceptions and belief in conspiracy theories on COVID-19 pandemic-related behaviours.

Throughout the COVID-19 pandemic, conspiracy theories about the virus spread rapidly, and whilst governments across the globe put in place different restrictions and guidelines to contain the pandemic, these were not universally adhered to. This research examined the association between pandemic related risk perceptions, belief in conspiracy theories, and compliance with COVID-19 public guidelines amongst a UK sample (n = 368). Participants rated their level of concern for a series of potential risks during the pandemic (to the economy, personal health, freedom, media integrity and health risk to others). Participants also rated their level of belief in different conspiracy theories and self-reported their behaviour during the first UK lockdown. Mediational analyses showed that stronger belief in conspiracy theories was associated with perceptions of lower risk to health and higher risk to the economy and freedom, which in turn were associated with lower compliance with COVID-19 related governmental guidelines. Perception of information transparency risks did not mediate the association between belief in conspiracy theories and compliant behaviours. These results highlight the key role that risk perception may play in translating belief in conspiracy theories into low compliance with governmental COVID-19 related guidelines. Our findings suggest new patterns with respect to the relationship between conspiracy theory adherence and salience of different risk perceptions amidst the pandemic, which could have implications for the development of public health messaging and communication interventions.

Effects of pyriproxyfen on zebrafish brain mitochondria and acetylcholinesterase.

Pyriproxyfen is an insecticide used worldwide that acts as a biomimetic of juvenile hormone. This study investigated metabolic and synaptic impairments triggered by pyriproxyfen using zebrafish acetylcholinesterase (zbAChE) and mitochondria as markers. A brain zbAChE assay was performed in vitro and in vivo covering a range of pyriproxyfen concentrations (0.001-10 µmol/L) to assess inhibition kinetics. Docking simulations were performed to characterize inhibitory interactions. Zebrafish male adults were acutely exposed to 0.001, 0.01 and 0.1 µg/mL pyriproxyfen for 16 h. Mitochondrial respiration of brain tissues was assessed. ROS generation was estimated using H2DCF-DA and MitoSOX. Calcium transport was monitored by Calcium Green™ 5 N. NO synthesis activity was estimated using DAF-FM-DA. Brain acetylcholinesterase showed an in vivo IC20 of 0.30 µmol/L pyriproxyfen, and an IC50 of 92.5 µmol/L. The inhibitory effect on zbAChE activity was competitive-like. Respiratory control of Complex I/II decreased significantly after insecticide exposure. The MitoSOX test showed that O2- generation had a pyriproxyfen dose-dependent effect. Brain tissue lost 50% of Ca2+ uptake capacity at 0.1 µg/mL pyriproxyfen. Ca2+ release showed a clear mitochondrial impairment at lower pyriproxyfen exposures. Thus, Ca2+ transport imbalance caused by pyriproxyfen may be a novel deleterious mechanism of action. Overall, the results showed that pyriproxyfen can compromise multiple and interconnected pathways: (1) zbAChE impairment and (2) the functioning of the electron transport chain, ROS generation and calcium homeostasis in zebrafish brain mitochondria. Considering the many similarities between zebrafish and human, more caution is needed when pyriproxyfen is used in both urban and agricultural pest control.

Mitochondria as targets for toxicity and metabolism research using zebrafish.

BACKGROUND: The study of mitochondrial functions in zebrafish was initiated before the 1990s and has effectively supported many of the recent scientific advances in the functional studies of mitochondria. SCOPE OF REVIEW: This work elaborates various peculiarities and general advances in the study of mitochondria using this animal model. MAJOR CONCLUSIONS: The inclusion of zebrafish models in scientific research was initiated with structural studies of mitochondria. Then, toxicological studies involving chemical compounds were undertaken. Currently, there is a decisive tendency to use zebrafish to understand how chemicals impair mitochondrial bioenergetics. Zebrafish modeling has been fruitful for the analysis of ion homeostasis, especially for Ca2+ transport, since zebrafish and mammals have the same set of Ca2+ transporters and mitochondrial membrane microdomains. Based on zebrafish embryo studies, our understanding of ROS generation has also led to new insights. GENERAL SIGNIFICANCE: For the study of mitochondria, a new era was begun with the inclusion of zebrafish in bioenergetics research.

Overlooked Leadership Potential: The Preference for Leadership Potential in Job Candidates Who Are Men vs. Women.

Two experiments tested the value people attach to the leadership potential and leadership performance of female and male candidates for leadership positions in an organizational hiring simulation. In both experiments, participants (Total N = 297) valued leadership potential more highly than leadership performance, but only for male candidates. By contrast, female candidates were preferred when they demonstrated leadership performance over leadership potential. The findings reveal an overlooked potential effect that exclusively benefits men and hinders women who pursue leadership positions that require leadership potential. Implications for the representation of women in leadership positions and directions for future research are discussed.

Endorsing and Reinforcing Gender and Age Stereotypes: The Negative Effect on Self-Rated Leadership Potential for Women and Older Workers.

Previous research has examined the impact of stereotypes on outcomes such as career progression and hiring decisions. We present a novel approach to examine the role of stereotypes in predicting self-rated leadership potential across gender and age groups. This research sheds light on the impact of leadership-incongruent and detrimental stereotypes about one's gender and age, for women and older workers, on self-ratings of leadership potential. Across three studies (total N = 640), correlational and experimental evidence shows differential effects of stereotypes about women (vs. men) and older (vs. younger) people on self-ratings of their own leadership potential. Results suggest that both gender and age stereotypes affect older workers more than their younger counterparts (Study 1). Specifically, effects on self-rated leadership potential at the intersectional level show that endorsement of stereotypes has opposite effects on older women to younger men (Study 1). Furthermore, stereotyped workplace cultures impacted women's and older worker's perceptions of job fit (Studies 2 and 3), also extending to job appeal for older workers (Study 3). Results are discussed in terms of career implications for both women and older workers, with a particular focus on older women, whose intersecting identities are leadership stereotype-incongruent.

Belief in conspiracy theories and intentions to engage in everyday crime.

Belief in conspiracy theories is associated with negative outcomes such as political disengagement, prejudice, and environmental inaction. The current studies - one cross-sectional (N = 253) and one experimental (N = 120) - tested the hypothesis that belief in conspiracy theories would increase intentions to engage in everyday crime. Study 1 demonstrated that belief in conspiracy theories predicted everyday crime behaviours when controlling for other known predictors of everyday crime (e.g., Honesty-Humility). Study 2 demonstrated that exposure to conspiracy theories (vs. control) increased intentions to engage in everyday crime in the future, through an increased feeling of anomie. The perception that others have conspired may therefore in some contexts lead to negative action rather than inaction.

Isatin Derivatives and Their Antiviral Properties Against Arboviruses: A Review.

Arboviruses have been spreading rapidly throughout the Western Hemisphere in recent decades. Among the arboviruses with high morbidity and mortality are the members of the Alphavirus and Flavivirus genera. Within the first genus, Chikungunya Virus (CHIKV) is considered one of the most challenging human arboviral infection worldwide, against which there is no specific antivirals. Flaviviruses are some of the main viruses responsible for encephalitis, haemorrhagic disease and developmental defects. Dengue virus (DENV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV) and Zika Virus (ZIKV) are examples of flaviviruses without clinically approved antiviral agents. Thus, the search for new antivirals becomes highly important. One of the strategies that can be employed to obtain new drugs is the identification and utilization of privileged structures. Isatin is an example of a privileged molecular framework, displaying a broad spectrum of biological activities, including antiviral action. Obtaining and studying the antiviral properties of isatin derivatives have helped to identify important agents with potential activity against different arboviruses. This article reviews some of these isatin derivatives, their structures and antiviral properties reported against this important group of viruses.

Surveillance or Self-Surveillance? Behavioral Cues Can Increase the Rate of Drivers' Pro-Environmental Behavior at a Long Wait Stop.

By leaving their engines idling for long periods, drivers contribute unnecessarily to air pollution, waste fuel, and produce noise and fumes that harm the environment. Railway level crossings are sites where many cars idle, many times a day. In this research, testing two psychological theories of influence, we examine the potential to encourage drivers to switch off their ignition while waiting at rail crossings. Two field studies presented different signs at a busy rail crossing site with a 2-min average wait. Inducing public self-focus (via a "Watching Eyes" stimulus) was not effective, even when accompanied by a written behavioral instruction. Instead, cueing a private-self focus ("think of yourself") was more effective, doubling the level of behavioral compliance. These findings confirm the need to engage the self when trying to instigate self-regulatory action, but that cues evoking self-surveillance may sometimes be more effective than cues that imply external surveillance.

Suspicion in the workplace: Organizational conspiracy theories and work-related outcomes.

Belief in conspiracy theories about societal events is widespread and has important consequences for political, health, and environmental behaviour. Little is known, however, about how conspiracy theorizing affects people's everyday working lives. In the present research, we predicted that belief in conspiracy theories about the workplace would be associated with increased turnover intentions. We further hypothesized that belief in these organizational conspiracy theories would predict decreased organizational commitment and job satisfaction. Finally, we hypothesized that these factors would mediate the relationship between organizational conspiracy theories and turnover intentions. In three studies (one correlational and two experiments, Ns = 209, 119, 202), we found support for these hypotheses. The current studies therefore demonstrate the potentially adverse consequences of conspiracy theorizing for the workplace. We argue that managers and employees should be careful not to dismiss conspiracy theorizing as harmless rumour or gossip.

The Cratylia mollis seed lectin induces membrane permeability transition in isolated rat liver mitochondria and a cyclosporine a-insensitive permeability transition in Trypanosoma cruzi mitochondria.

Previous results provided evidence that Cratylia mollis seed lectin (Cramoll 1,4) promotes Trypanosoma cruzi epimastigotes death by necrosis via a mechanism involving plasma membrane permeabilization to Ca(2+) and mitochondrial dysfunction due to matrix Ca(2+) overload. In order to investigate the mechanism of Ca(2+) -induced mitochondrial impairment, experiments were performed analyzing the effects of this lectin on T. cruzi mitochondrial fraction and in isolated rat liver mitochondria (RLM), as a control. Confocal microscopy of T. cruzi whole cell revealed that Cramoll 1,4 binding to the plasma membrane glycoconjugates is followed by its internalization and binding to the mitochondrion. Electrical membrane potential (∆Ψm ) of T. cruzi mitochondrial fraction suspended in a reaction medium containing 10 µM Ca(2+) was significantly decreased by 50 µg/ml Cramoll 1,4 via a mechanism insensitive to cyclosporine A (CsA, membrane permeability transition (MPT) inhibitor), but sensitive to catalase or 125 mM glucose. In RLM suspended in a medium containing 10 µM Ca(2+) this lectin, at 50 µg/ml, induced increase in the rate of hydrogen peroxide release, mitochondrial swelling, and ∆Ψm disruption. All these mitochondrial alterations were sensitive to CsA, catalase, and EGTA. These results indicate that Cramoll 1, 4 leads to inner mitochondrial membrane permeabilization through Ca(2+) dependent mechanisms in both mitochondria. The sensitivity to CsA in RLM characterizes this lectin as a MPT inducer and the lack of CsA effect identifies a CsA-insensitive MPT in T. cruzi mitochondria.

Isoswertisin flavones and other constituents from Peperomia obtusifolia.

A phytochemical investigation of the leaves and stems of Peperomia obtusifolia (Piperaceae) yielded a new flavone C-diglycoside isoswertisin-4'-methyl-ether-2''α-L-rhamnoside (1), along with four known compounds: isoswertisin-2''α-L-rhamnoside (2), (+)-diayangambin (3), 2-episesalatin (4) and corchoionoside C (5). The structures of the two flavone C-diglycosides (1, 2) were elucidated on the basis of 1D and 2D NMR spectroscopy and MS spectrometric data. These flavones were evaluated by bioautographic assay against Cladosporium cladosporioides and C. sphaerospermum and showed weak antifungal activity.

Trypanocidal activity of flavonoids and limonoids isolated from Myrsinaceae and Meliaceae active plant extracts / Atividade tripanocida de flavonoides e limonoides isolados de extratos ativos de plantas de Myrsinaceae e Meliaceae

The activity of crude extracts of three Rapanea species (Myrsinaceae) and Cipadessa fruticosa (Meliaceae) was evaluated in vitro against the trypomastigote forms of Trypanosoma cruzi. Thirty-three extracts from different organs of these species were assayed and eleven of them showed significant activity (lysis percent >50). The fractionation of an active extract from branches of R. lancifolia (99.5 percent) led to the isolation of two flavonoids: quercetin and taxifolin, which have weak trypanocidal activity. Additionally, one active extract from fruits of C. fruticosa (97.7 percent) afforded mexicanolide limonoids: cipadesin, mexicanolide, febrifugin and cipadesin A, that were slightly active on T. cruzi. Moreover, other two flavonoids (flavone and 7-methoxyflavone), previously assayed against T. cruzi, were isolated from the hexane extract from branches of C. fruticosa (100 percent). The results presented here suggest that the plants evaluated could be a source of new active compounds against T. cruzi.

A atividade de extratos brutos de três espécies de Rapanea (Myrsinaceae) e de Cipadessa fruticosa (Meliaceae) foi avaliada in vitro contra formas tripomastigotas de Trypanosoma cruzi. Foram obtidos 33 extratos de diferentes órgãos das espécies estudadas, sendo que onze deles apresentaram atividades significantes ( por cento de lise > 50) nos ensaios realizados. O fracionamento de um extrato ativo dos galhos de R. lancifolia (99,5 por cento) resultou no isolamento de dois flavonoides (quercetina e taxifolina), que apresentaram baixa atividade tripanocida. De um extrato ativo dos frutos de C. fruticosa (97,7 por cento) foram isolados os limonoides mexicanolídeos cipadesina, mexicanolídeo, febrifugina e cipadesina A, que foram moderadamente ativos sobre T. cruzi. Além disso, outros dois flavonoides (flavona e 7-metoxiflavona), previamente ensaiados contra T. cruzi, foram isolados do extrato hexânico dos galhos de C. fruticosa (100 por cento). Os resultados obtidos aqui sugerem que as plantas avaliadas podem constituir fontes de novas substâncias ativas sobre o T. cruzi.

Effects of limonoids from Cipadessa fruticosa on fall armyworm.

Six mexicanolide limonoids isolated from the dichloromethane extract of the fruits of Cipadessa fruticosa Blume (Meliaceae) were evaluated against Spodoptera frugiperda (J. E. Smith). Gedunin was used as a positive control. When incorporated into an artificial diet of neonates at 50.0 mg kg(-1), febrifugin A showed 73.3% mortality. All the compounds showed moderate insecticidal activity, except for ruageanin A, when compared with the control. Febrifugin also showed growth inhibition and antifeedant activities (at 100.0 mg kg(-1)). The correlation between the insecticidal activity of the isolated compounds and their chemical structure was discussed.

Screening of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase enzyme inhibitors / Busca de inibidores da enzima glicossomal gliceraldeído 3-fosfato desidrogenase de Trypanosoma cruzi

The inhibitory activity of crude extracts of Meliaceae and Rutaceae plants on glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) enzyme from Trypanosoma cruzi was evaluated at 100 μg/mL. Forty-six extracts were tested and fifteen of them showed significant inhibitory activity (IA percent > 50). The majority of the assayed extracts of Meliaceae plants (Cedrela fissilis, Cipadessa fruticosa and Trichilia ramalhoi) showed high ability to inhibit the enzymatic activity. The fractionation of the hexane extract from branches of C. fruticosa led to the isolation of three flavonoids: flavone, 7-methoxyflavone and 3',4',5',5,7-pentamethoxyflavone. The two last compounds showed high ability to inhibit the gGAPDH activity. Therefore, the assayed Meliaceae species could be considered as a promising source of lead compounds against Chagas' disease.

Nesse trabalho foi avaliada a atividade inibitória sobre a enzima glicossomal gliceraldeído-3-fosfato desidrogenase de T. cruzi (gGAPDH) de extratos vegetais oriundos de plantas das famílias Meliaceae e Rutaceae, na concentração de 100 μg/mL. Foram testados 46 extratos, dos quais 15 apresentaram atividade inibitória significativa ( por cento AI > 50). A maioria dos extratos de plantas da família Meliaceae (Cedrela fissilis, Cipadessa fruticosa e Trichilia ramalhoi) apresentou grande potencial em inibir a atividade enzimática. O fracionamento do extrato hexânico dos galhos de C. fruticosa permitiu o isolamento de três flavonóides: flavona, 7-metoxiflavona e 3',4',5',5,7-pentametoxiflavona. Os dois últimos foram ativos na inibição da atividade de gGAPDH. Desta forma, as três espécies de Meliaceae testadas podem ser consideradas promissoras na busca de compostos protótipos para o controle da doença de Chagas.

Novel nitrofurazone derivatives endowed with antimicrobial activity.

The N-alkylated derivatives from nitrofurazone were synthesised and evaluated in vitro for their efficacy as antimicrobial agents against representative strains, including methicillin-resistant Staphylococcus aureus (MRSA). The derivative 2a demonstrated greater activity than the prototype and was comparable to currently used antimicrobial drugs.