Acaricide Flupentiofenox Inhibits the Mitochondrial ß-Oxidation Pathway of Fatty Acids.

A newly developed pesticide, flupentiofenox, has a unique trifluoroethyl phenylsulfoxide structure, and it powerfully affects spider mites, including those with resistance to multiple commercial acaricides. To clarify the mode of action of flupentiofenox, we investigated its effect on mitochondrial energy generation. We observed that flupentiofenox decreased adenosine triphosphate (ATP) levels in two-spotted spider mites (Tetranychus urticae) at a practical dose. Flupentiofenox potently inhibited mitochondrial oxygen consumption under conditions of palmitoyl-carnitine or octanoic acid supply, but not under conditions of pyruvate supply. These results show that flupentiofenox inhibits the mitochondrial fatty acid metabolic pathway between the uptake of long-chain acylcarnitine or medium-chain fatty acid and the synthesis of acetyl-CoA by ß-oxidation, resulting in suppressed mitochondrial energy generation. Our investigations have led us to conclude that flupentiofenox is a pesticide with a novel mode of action.

Structural Simplification of Podophyllotoxin: Discovery of γ-Butyrolactone Derivatives as Novel Antiviral Agents for Plant Protection.

Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin's structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3g demonstrating the most potent in vivo anti-TMV activity. At 500 µg/mL, compound 3g achieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycin and ribavirin. Notably, the syn-diastereomer (syn-3g) exhibited superior antiviral activity compared to the anti-diastereomer (anti-3g). Mechanistic studies revealed that syn-3g could bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g, with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.

Understanding the evolution of macrolides resistance: a mini review.

BACKGROUND: Macrolides inhibit the growth of bacterial cells by preventing the elongation of polypeptides during protein biosynthesis and includes natural, synthetic, and semisynthetic products. This occurs by blocking the passage of the polypeptide chain as macrolides bind at the nascent peptide exit tunnel. OBJECTIVE: Recent data of ribosome profiling via ribo-seq further proves that other than blocking the polypeptide chain, macrolides are also able to affect the synthesis of individual proteins. Thus, this shows that the mode of action of macrolides is more complex than we initially thought. Since the discovery of macrolides in the 1950s, they have been widely used in veterinary, agriculture, and medicine. Due to misuse and overuse of antibiotics; bacteria have acquired resistance against them. Hence, it is of utmost importance for us to fully understand the mode of action of macrolides as well as the mechanism of resistance against macrolides to mitigate the antibiotic resistance issues. CONTENT: With a better understanding on the mode of actions of macrolides, chemical modifications can be performed to improve its potency. Furthermore, the complete detailed understanding of the mode of action of macrolides remained vague as new findings challenged the theory that was already in existence - due to this obscurity, research into macrolides' mode of action continues up to this day. CONCLUSION: In this review, we present an overview of macrolide antibiotics with the emphasis on the latest knowledge regarding the mode of action of macrolides and mechanism of resistance employed in bacteria against macrolides.

Design, synthesis, and biological activities of arecoline derivatives containing 1,3,4-oxadiazole structure.

Pesticides play an important role in the development of agriculture, as they can prevent and control crop diseases and pests, improve crop yield and quality. However, the abuse and improper use of pesticides can lead to negative impacts such as environmental pollution and pest resistance issues. There is an urgent need to develop green, safe, and efficient pesticides. In this work, natural product arecoline was selected as parent structure, a series of arecoline derivatives were designed, synthesized, and systematically investigated antiviral activities against tobacco mosaic virus (TMV). These compounds were found to have good to excellent anti-TMV activities for the first time. The antiviral activities of 4a, 4 h, 4 l, 4p, 6a, 6c, and 6f are higher than that of ningnanmycin. Compounds 4 h (EC50 value 146 µg/mL) and 4p (EC50 value 161 µg/mL) with simple structures and excellent activities emerged as new antiviral candidates. We chose 4 h to further investigate the antiviral mechanism, which revealed that it can cause virus fragmentation by acting on the viral coat protein (CP). We further validated this result through molecular docking. These compounds also displayed broad-spectrum fungicidal activities against 8 plant pathogenic fungi. This work lays the theoretical foundation for the application of arecoline derivatives in the agricultural field.

Mode of action of dieldrin-induced liver tumors: application to human risk assessment.

Dieldrin is an organochlorine insecticide that was widely used until 1970 when its use was banned because of its liver carcinogenicity in mice. Several long-term rodent bioassays have reported dieldrin to induce liver tumors in in several strains of mice, but not in rats. This article reviews the available information on dieldrin liver effects and performs an analysis of mode of action (MOA) and human relevance of these liver findings. Scientific evidence strongly supports a MOA based on CAR activation, leading to alterations in gene expression, which result in increased hepatocellular proliferation, clonal expansion leading to altered hepatic foci, and ultimately the formation of hepatocellular adenomas and carcinomas. Associative events include increased liver weight, centrilobular hypertrophy, increased expression of Cyp2b10 and its resulting increased enzymatic activity. Other associative events include alterations of intercellular gap junction communication and oxidative stress. Alternative MOAs are evaluated and shown not to be related to dieldrin administration. Weight of evidence shows that dieldrin is not DNA reactive, it is not mutagenic, and it is not genotoxic in general. Furthermore, activation of other pertinent nuclear receptors, including PXR, PPARα, AhR, and estrogen are not related to dieldrin-induced liver tumors nor is there liver cytotoxicity. In previous studies, rats, dogs, and non-human primates did not show increased cell proliferation or production of pre-neoplastic or neoplastic lesions following dieldrin treatment. Thus, the evidence strongly indicates that dieldrin-induced mouse liver tumors are due to CAR activation and are specific to the mouse, which are qualitatively not relevant to human hepatocarcinogenesis. Thus, there is no carcinogenic risk to humans. This conclusion is also supported by a lack of positive epidemiologic findings for evidence of liver carcinogenicity. Based on current understanding of the mode of action of dieldrin-induced liver tumors in mice, the appropriate conclusion is that dieldrin is a mouse specific liver carcinogen and it does not pose a cancer risk to humans.

Indole Compounds in Oncology: Therapeutic Potential and Mechanistic Insights.

Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research.

The Spectrum of CAR Cellular Effectors: Modes of Action in Anti-Tumor Immunity.

Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation.

In vivo movement of retinoblastoma-related protein (RBR) towards cytoplasm during mitosis in Arabidopsisthaliana.

Retinoblastoma protein is central in signaling networks of fundamental cell decisions such as proliferation and differentiation in all metazoans and cancer development. Immunostaining and biochemical evidence demonstrated that during interphase retinoblastoma protein is in the nucleus and is hypophosphorylated, and during mitosis is in the cytoplasm and is hyperphosphorylated. The purpose of this study was to visualize in vivo in a non-diseased tissue, the dynamic spatial and temporal nuclear exit toward the cytoplasm of this protein during mitosis and its return to the nucleus to obtain insights into its potential cytosolic functions. Using high-resolution time-lapse images from confocal microscopy, we tracked in vivo the ortholog in plants the RETINOBLASTOMA RELATED (RBR) protein tagged with Green Fluorescent Protein (GFP) in Arabidopsis thaliana's root. RBR protein exits from dense aggregates in the nucleus before chromosomes are in prophase in less than 2 min, spreading outwards as smaller particles projected throughout the cytosol during mitosis like a diffusive yet controlled event until telophase, when the daughter's nuclei form; RBR returns to the nuclei in coordination with decondensing chromosomal DNA forming new aggregates again in punctuated larger structures in each corresponding nuclei. We propose RBR diffused particles in the cytoplasm may function as a cytosolic sensor of incoming signals, thus coordinating re-aggregation with DNA is a mechanism by which any new incoming signals encountered by RBR may lead to a reconfiguration of the nuclear transcriptomic context. The small RBR diffused particles in the cytoplasm may preserve topologic-like properties allowing them to aggregate and restore their nuclear location, they may also be part of transient cytoplasmic storage of the cellular pre-mitotic transcriptional context, that once inside the nuclei may execute both the pre mitosis transcriptional context as well as new transcriptional instructions.

Investigating Antiprotozoal Chemotherapies with Novel Proteomic Tools-Chances and Limitations: A Critical Review.

Identification of drug targets and biochemical investigations on mechanisms of action are major issues in modern drug development. The present article is a critical review of the classical "one drug"-"one target" paradigm. In fact, novel methods for target deconvolution and for investigation of resistant strains based on protein mass spectrometry have shown that multiple gene products and adaptation mechanisms are involved in the responses of pathogens to xenobiotics rather than one single gene or gene product. Resistance to drugs may be linked to differential expression of other proteins than those interacting with the drug in protein binding studies and result in complex cell physiological adaptation. Consequently, the unraveling of mechanisms of action needs approaches beyond proteomics. This review is focused on protozoan pathogens. The conclusions can, however, be extended to chemotherapies against other pathogens or cancer.

Styrene lung cancer risk assessment: an alternative evaluation of human lung cancer risk assuming mouse lung tumors are potentially human relevant and operating by a threshold-based non-genotoxic mode of action.

Rodent inhalation studies indicate styrene is a mouse lung-specific carcinogen. Mode-of-action (MOA) analyses indicate that the lung tumors cannot be excluded as weakly quantitatively relevant to humans due to shared oxidative metabolites detected in rodents and humans. However, styrene also is not genotoxic following in vivo dosing. The objective of this review was to characterize occupational and general population cancer risks by conservatively assuming mouse lung tumors were relevant to humans but operating by a non-genotoxic MOA. Inhalation cancer values reference concentrations for respective occupational and general population exposures (RfCcar-occup and RfCcar-genpop) were derived from initial benchmark dose (BMD) modeling of mouse inhalation tumor dose-response data. An overall lowest BMDL10 of 4.7 ppm was modeled for lung tumors, which was further duration- and dose-adjusted by physiologically based pharmacokinetic (PBPK) modeling to derive RfCcar-occup/genpop values of 6.2 ppm and 0.8 ppm, respectively. With the exception of open-mold fiber reinforced composite workers not using personal protective equipment (PPE), the RfCcar-occup/genpop values are greater than typical occupational and general population human exposures, thus indicating styrene exposures represent a low potential for human lung cancer risk. Consistent with this conclusion, a review of styrene occupational epidemiology did not support a conclusion of an association between styrene exposure and lung cancer occurrence, and further supports a conclusion that the conservatively derived RfCcar-occup is lung cancer protective.

Memory effects of prior subculture may impact the quality of multiomic perturbation profiles.

Mass spectrometry-based omics technologies are increasingly used in perturbation studies to map drug effects to biological pathways by identifying significant molecular events. Significance is influenced by fold change and variation of each molecular parameter, but also by multiple testing corrections. While the fold change is largely determined by the biological system, the variation is determined by experimental workflows. Here, it is shown that memory effects of prior subculture can influence the variation of perturbation profiles using the two colon carcinoma cell lines SW480 and HCT116. These memory effects are largely driven by differences in growth states that persist into the perturbation experiment. In SW480 cells, memory effects combined with moderate treatment effects amplify the variation in multiple omics levels, including eicosadomics, proteomics, and phosphoproteomics. With stronger treatment effects, the memory effect was less pronounced, as demonstrated in HCT116 cells. Subculture homogeneity was controlled by real-time monitoring of cell growth. Controlled homogeneous subculture resulted in a perturbation network of 321 causal conjectures based on combined proteomic and phosphoproteomic data, compared to only 58 causal conjectures without controlling subculture homogeneity in SW480 cells. Some cellular responses and regulatory events were identified that extend the mode of action of arsenic trioxide (ATO) only when accounting for these memory effects. Controlled prior subculture led to the finding of a synergistic combination treatment of ATO with the thioredoxin reductase 1 inhibitor auranofin, which may prove useful in the management of NRF2-mediated resistance mechanisms.

A UK framework for the assessment and integration of different scientific evidence streams in chemical risk assessment.

BACKGROUND: Few methods are available for transparently combining different evidence streams for chemical risk assessment to reach an integrated conclusion on the probability of causation. Hence, the UK Committees on Toxicity (COT) and on Carcinogenicity (COC) have reviewed current practice and developed guidance on how to achieve this in a transparent manner, using graphical visualisation. METHODS/APPROACH: All lines of evidence, including toxicological, epidemiological, new approach methodologies, and mode of action should be considered, taking account of their strengths/weaknesses in their relative weighting towards a conclusion on the probability of causation. A qualitative estimate of the probability of causation is plotted for each line of evidence and a combined estimate provided. DISCUSSION/CONCLUSIONS: Guidance is provided on integration of multiple lines of evidence for causation, based on current best practice. Qualitative estimates of probability for each line of evidence are plotted graphically. This ensures a deliberative, consensus conclusion on likelihood of causation is reached. It also ensures clear communication of the influence of the different lines of evidence on the overall conclusion on causality. Issues on which advice from the respective Committees is sought varies considerably, hence the guidance is designed to be sufficiently flexible to meet this need.

Bioactive Streptomycetes: A Powerful Tool to Synthesize Diverse Nanoparticles With Multifarious Properties.

Nanobiotechnology has gained significant attention due to its capacity to generate substantial benefits through the integration of microbial biotechnology and nanotechnology. Among microbial organisms, Actinomycetes, particularly the prominent genus Streptomycetes, have garnered attention for their prolific production of antibiotics. Streptomycetes have emerged as pivotal contributors to the discovery of a substantial number of antibiotics and play a dominant role in combating infectious diseases on a global scale. Despite the noteworthy progress achieved through the development and utilization of antibiotics to combat infectious pathogens, the prevalence of infectious diseases remains a prominent cause of mortality worldwide, particularly among the elderly and children. The emergence of antibiotic resistance among pathogens has diminished the efficacy of antibiotics in recent decades. Nevertheless, Streptomycetes continue to demonstrate their potential by producing bioactive metabolites for the synthesis of nanoparticles. Streptomycetes are instrumental in producing nanoparticles with diverse bioactive characteristics, including antiviral, antibacterial, antifungal, antioxidant, and antitumor properties. Biologically synthesized nanoparticles have exhibited a meaningful reduction in the impact of antibiotic resistance, providing resources for the development of new and effective drugs. This review succinctly outlines the significant applications of Streptomycetes as a crucial element in nanoparticle synthesis, showcasing their potential for diverse and enhanced beneficial applications.

Assessment of the genotoxicity of tert-butyl alcohol in an in vivo thyroid comet assay.

Chronic exposure to high (20,000 ppm) concentrations of tert-butyl alcohol (TBA) in drinking water, equivalent to ~2100 mg/kg bodyweight per day, is associated with slight increases in the incidence of thyroid follicular cell adenomas and carcinomas in mice, with no other indications of carcinogenicity. In a recent toxicological review of TBA, the U.S. EPA determined that the genotoxic potential of TBA was inconclusive, largely based on non-standard studies such as in vitro comet assays. As such, the potential role of genotoxicity in the mode of action of thyroid tumors and therefore human relevance was considered uncertain. To address the potential role of genotoxicity in TBA-associated thyroid tumor formation, CD-1 mice were exposed up to a maximum tolerated dose of 1500 mg/kg-day via oral gavage for two consecutive days and DNA damage was assessed with the comet assay in the thyroid. Blood TBA levels were analyzed by headspace GC-MS to confirm systemic tissue exposure. At study termination, no significant increases (DNA breakage) or decreases (DNA crosslinks) in %DNA tail were observed in TBA exposed mice. In contrast, oral gavage of the positive control ethyl methanesulfonate significantly increased %DNA tail in the thyroid. These findings are consistent with most genotoxicity studies on TBA and provide mechanistic support for non-linear, threshold toxicity criteria for TBA. While the mode of action for the thyroid tumors remains unclear, linear low dose extrapolation methods for TBA appear more a matter of policy than science.

Exploring the Biochemical and Nutra-Pharmaceutical Prospects of Some Thymus Species - A Review.

The Thymus genus includes various medicinal and aromatic species, cultivated worldwide for their unique medicinal and economic value. Besides, their conventional use as a culinary flavoring agent, Thymus species are well-known for their diverse biological effects, such as antioxidant, anti-fungal, anti-bacterial, anti-viral, anti-tumor, anti-inflammatory, anti-cancer, and anti-hypertensive properties. Hence, they are used in the treatment of fever, colds, and digestive and cardiovascular diseases. The pharmaceutical significance of Thymus plants is due to their high levels of bioactive components such as natural terpenoid phenol derivatives (p-cymene, carvacrol, thymol, geraniol), flavonoids, alkaloids, and phenolic acids. This review examines the phytochemicals, biological properties, functional food, and nutraceutical attributes of some important Thymus species, with a specific focus on their potential uses in the nutra-pharmaceutical industries. Furthermore, the review provides an insight into the mechanisms of biological activities of key phytochemicals of Thymus species exploring their potential for the development of novel natural drugs.

Exploring the frontiers of therapeutic breadth of antifungal peptides: A new avenue in antifungal drugs.

The growing prevalence of fungal infections alongside rising resistance to antifungal drugs poses a significant challenge to public health safety. At the close of the 2000s, major pharmaceutical firms began to scale back on antimicrobial research due to repeated setbacks and diminished economic gains, leaving only smaller companies and research labs to pursue new antifungal solutions. Among various natural sources explored for novel antifungal compounds, antifungal peptides (AFPs) emerge as particularly promising. Despite their potential, AFPs receive less focus than their antibacterial counterparts. These peptides have been sourced extensively from nature, including plants, animals, insects, and especially bacteria and fungi. Furthermore, with advancements in recombinant biotechnology and computational biology, AFPs can also be synthesized in lab settings, facilitating peptide production. AFPs are noted for their wide-ranging efficacy, in vitro and in vivo safety, and ability to combat biofilms. They are distinguished by their high specificity, minimal toxicity to cells, and reduced likelihood of resistance development. This review aims to comprehensively cover AFPs, including their sources-both natural and synthetic-their antifungal and biofilm-fighting capabilities in laboratory and real-world settings, their action mechanisms, and the current status of AFP research. ONE-SENTENCE SUMMARY: This comprehensive review of AFPs will be helpful for further research in antifungal research.

Mode of action analysis for fluxapyroxad-induced rat liver tumour formation: evidence for activation of the constitutive androstane receptor and assessment of human relevance.

The fungicide fluxapyroxad (BAS 700 F) has been shown to significantly increase the incidence of liver tumours in male Wistar rats at dietary levels of 1500 and 3000 ppm and in female rats at a dietary level of 3000 ppm via a non-genotoxic mechanism. In order to elucidate the mode of action (MOA) for fluxapyroxad-induced rat liver tumour formation a series of in vivo and in vitro investigative studies were undertaken. The treatment of male and female Wistar rats with diets containing 0 (control), 50, 250, 1500 and 3000 ppm fluxapyroxad for 1, 3, 7 and 14 days resulted in a dose-dependent increases in relative weight at 1500 and 3000 ppm from day 3 onwards in both sexes, with an increase in relative liver weight being also observed in male rats given 250 ppm fluxapyroxad for 14 days. Examination of liver sections revealed a centrilobular hepatocyte hypertrophy in some fluxapyroxad treated male and female rats. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 1500 and 3000 ppm fluxapyroxad for 3 and 7 days and in female rats given 50-3000 ppm fluxapyroxad for 7 days and 250-3000 ppm fluxapyroxad for 3 and 14 days; the maximal increases in RDS in both sexes being observed after 7 days treatment. The treatment of male and female Wistar rats with 250-3000 ppm fluxapyroxad for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content and CYP2B subfamily-dependent enzyme activities. Male Wistar rat hepatocytes were treated with control medium and medium containing 1-100 µM fluxapyroxad or 500 µM sodium phenobarbital (NaPB) for 4 days. Treatment with fluxapyroxad and NaPB increased CYP2B and CYP3A enzyme activities and mRNA levels but had little effect on markers of CYP1A and CYP4A subfamily enzymes and of the peroxisomal fatty acid ß-oxidation cycle. Hepatocyte RDS was significantly increased by treatment with fluxapyroxad, NaPB and 25 ng/ml epidermal growth factor (EGF). The treatment of hepatocytes from two male human donors with 1-100 µM fluxapyroxad or 500 µM NaPB for 4 days resulted in some increases in CYP2B and CYP3A enzyme activities and CYP mRNA levels but had no effect on hepatocyte RDS, whereas treatment with EGF resulted in significant increase in RDS in both human hepatocyte preparations. Hepatocytes from male Sprague-Dawley wild type (WT) and constitutive androstane receptor (CAR) knockout (CAR KO) rats were treated with control medium and medium containing 1-16 µM fluxapyroxad or 500 µM NaPB for 4 days. While both fluxapyroxad and NaPB increased CYP2B enzyme activities and mRNA levels in WT hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both fluxapyroxad and NaPB only increased RDS in WT and not in CAR KO rat hepatocytes, whereas treatment with EGF increased RDS in both WT and CAR KO rat hepatocytes. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that fluxapyroxad is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for fluxapyroxad-induced rat liver tumour formation has been established. Based on the lack of effect of fluxapyroxad on RDS in human hepatocytes, it is considered that the MOA for fluxapyroxad-induced liver tumour formation is qualitatively not plausible for humans.

Flavonoids as Insecticides in Crop Protection-A Review of Current Research and Future Prospects.

Pesticide overuse in agricultural systems has resulted in the development of pest resistance, the impoverishment of soil microbiota, water pollution, and several human health issues. Nonetheless, farmers still depend heavily on these agrochemicals for economically viable production, given the high frequency at which crops are affected by pests. Phytopathogenic insects are considered the most destructive pests on crops. Botanical pesticides have gained attention as potential biopesticides and complements to traditional pesticides, owing to their biodegradability and low toxicity. Plant-based extracts are abundant in a wide variety of bioactive compounds, such as flavonoids, a class of polyphenols that have been extensively studied for this purpose because of their involvement in plant defense responses. The present review offers a comprehensive review of current research on the potential of flavonoids as insecticides for crop protection, addressing the modes and possible mechanisms of action underlying their bioactivity. The structure-activity relationship is also discussed. It also addresses challenges associated with their application in pest and disease management and suggests alternatives to overcome these issues.

Integrative investigation of hematotoxic effects induced by low doses of lead, cadmium, mercury and arsenic mixture: In vivo and in silico approach.

The effect of the lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) mixture (MIX) on hematotoxicity development was investigated trough combined approach. In vivo subacute study (28 days) was performed on rats (5 per group): a control group and five groups orally exposed to increasing metal(loid) mixture doses, MIX 1- MIX 5 (mg/kg bw./day) (Pb: 0.003, 0.01, 0.1, 0.3, 1; Cd: 0.01, 0.03, 0.3, 0.9, 3; Hg: 0.0002, 0.0006, 0.006, 0.018, 0.06; As: 0.002, 0.006, 0.06, 0.18, 0.6). Blood was taken for analysis of hematological parameters and serum iron (Fe) analysis. MIX treatment increased thrombocyte/platelet count and MCHC and decreased Hb, HCT, MCV and MCH values compared to control, indicating the development of anemia and thrombocytosis. BMDIs with the narrowest width were identified for MCH [pg] (6.030E-03 - 1.287E-01 mg Pb/kg bw./day; 2.010E-02 - 4.290E-01 mg Cd/kg bw./day; 4.020E-04 - 8.580E-03 mg Hg/kg bw./day; 4.020E-03 - 8.580E-02 mg As/kg bw./day). In silico analysis showed target genes connected with MIX and the development of: anemia - ACHE, GSR, PARP1, TNF; thrombocytosis - JAK2, CALR, MPL, THPO; hematological diseases - FAS and ALAD. The main extracted pathways for anemia were related to apoptosis and oxidative stress; for thrombocytosis were signaling pathways of Jak-STAT and TPO. Changes in miRNAs and transcription factors enabled the mode of action (MoA) development based on the obtained results, contributing to mechanistic understanding and hematological risk related to MIX exposure.

Desarrollo de categorías del modo de actuación creativo en estudiantes universitarios

Introducción: Es importante la relación entre el desarrollo de las categorías originalidad, flexibilidad, autonomía y motivación del modo de actuación creativo. El objetivo del artículo consistió en elaborar un sistema de indicaciones para el desarrollo de categorías del modo de actuación creativo en estudiantes universitarios. Métodos: Se realizó una investigación mixta, donde el universo lo constituyeron estudiantes de la carrera de Pedagogía-Sicología de la Universidad de Sancti Spíritus "José Martí Pérez" en el curso 2021-2022 y se tomó una muestra aleatoria intencional de 24 educandos del tercer año. Resultados: El procesamiento estadístico de los instrumentos aplicados permitió ubicar al 75 % de la muestra entre un nivel medio y bajo en el desarrollo de categorías del modo de actuación creativo, por carencias en su expresión. Discusión: Desde fundamentos teóricos referenciados se analizó una propuesta de indicaciones que permiten la sistematización de contenidos de aprendizaje y facilitan el desarrollo de acciones autónomas y motivadoras para solucionar problemáticas en el contexto laboral. Conclusiones: La elaboración de indicaciones, desde la disciplina principal integradora y en estrecha relación con las categorías declaradas del modo de actuación creativo, facilitaron su desarrollo y demostraron pertinencia y factibilidad en el contexto de la práctica laboral.

Introduction: The relationship between the development of the categories of originality, flexibility, autonomy and motivation of the creative mode of action is important. The objective of the article was to develop a system of indications for the development of categories of the creative mode of action in university students. Methods: A mixed investigation was carried out, where the universe was made up of students of the Pedagogy-Psychology degree at the University of Sancti Spíritus "José Martí Pérez" in the 2021-2022 academic year and an intentional random sample of 24 students from the third year was taken. In the research, actions were designed to solve problems in work practice and a self-assessment scale about the development of the categories of the creative mode of action. Results: The statistical processing of the applied instruments allowed 75 % of the sample to be placed between a medium and low level in the development of categories of the creative mode of action, due to deficiencies in its expression. Discussion: From referenced theoretical foundations, a proposal of indications was analyzed that allow the systematization of learning content and facilitate the development of autonomous and motivating actions to solve problems in the work context. Conclusions: The development of indications, from the main integrative discipline and in close relationship with the declared categories of the creative mode of action, facilitated its development and demonstrated relevance and feasibility in the context of work practice.