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Catarina Roma-Rodrigues, Alexandra R Fernandes, Pedro V BaptistaUCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, Caparica 2829-516, PortugalCorrespondence: Alexandra R Fernandes; Pedro V BaptistaUCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, Caparica 2829-516, PortugalTel +351 21 294 8530Fax +351 21 294 8530Email ma.fernandes@fct.unl.pt pmvb@fct.unl.ptPurpose: Progression of chronic myeloid leukemia (CML) is frequently associated with increased angiogenesis at the bone marrow mediated by exosomes. The capability of gold nanoparticles (AuNPs) functionalized with antiangiogenic peptides to hinder the formation of new blood vessels has been demonstrated in a chorioallantoic membrane (CAM) model.Methods: Exosomes of K562 CML cell line were isolated and their angiogenic effect assessed in a CAM model. AuNPs functionalized with antiangiogenic peptides were used to block the angiogenic effect of CML-derived exosomes, assessed by evaluation of expression levels of key modulators involved in angiogenic pathways - VEGFA, VEGFR1 (also known as FLT1) and IL8.Results: Exosomes isolated from K562 cells promoted the doubling of newly formed vessels associated with the increase of VEGFR1 expression. This is a concentration and time-dependent effect. The AuNPs functionalized with antiangiogenic peptides were capable to block the angiogenic effect by modulating VEGFR1 associated pathway.Conclusion: Exosomes derived from blast cells are capable to trigger (neo)-angiogenesis, a key factor for the progression and spreading of cancer, in particular in CML. AuNPs functionalized with specific antiangiogenic peptides are capable to block the effect of the exosomes produced by malignant cells via modulation of the intrinsic VEGFR pathway. Together, these data highlight the potential of nanomedicine-based strategies against cancer proliferation.Keywords: chronic myeloid leukemia, exosomes, chorioallantoic membrane, gold nanoparticles, angiogenesis

Raquel Vinhas,1 Alexandra Lourenço,2 Susana Santos,2 Marcos Lemos,2 Patrícia Ribeiro,2 Aida Botelho de Sousa,2 Pedro Viana Baptista,1 Alexandra Ramos Fernandes1 1UCIBIO, Life Sciences Department, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal; 2Hematology Service, Hospital dos Capuchos (CHLC), Lisbon, Portugal Abstract: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) represents the most common genetic subtype of adult ALL (20%–30%) and accounts for approximately 50% of all cases in the elderly. It has been considered the subgroup of ALL with the worst outcome. The introduction of tyrosine kinase inhibitors (TKIs) allows complete hematologic remission virtually in all patients, with improved disease-free survival and overall survival. Nevertheless, the emergence of resistant mutations in BCR-ABL1 may require different TKI strategies to overcome the patient’s resistance and disease relapse. Here, we report a Ph+ B-ALL case with persistent minimal residual disease (MRD) after treatment with dasatinib. The patient expressed the P190BCR-ABL1 isoform and a novel BCR-ABL1 mutation, p.Y440C. The latter is in the C-terminal lobe of the kinase domain, which likely induces deviations in the protein structure and activity and destabilizes its inactive conformation. The treatment was substituted by bosutinib, which binds to the active conformation of the protein, prior to allogeneic bone marrow transplant to overcome the lack of a complete response to dasatinib. These findings strengthen the importance of BCR-ABL1 mutational screening in Ph+ patients, particularly for those who do not achieve complete molecular remission. Keywords: ALL, Philadelphia chromosome, e14a2, mutation, p.Y440C

Catarina Roma-Rodrigues,1 Amelie Heuer-Jungemann,2 Alexandra R Fernandes,1 Antonios G Kanaras,2 Pedro V Baptista1 1UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal; 2Institute for Life Sciences, Physics and Astronomy, Faculty of Physical Sciences and Engineering, University of Southampton, Southampton, UK Abstract: In this work, peptides designed to selectively interact with cellular receptors involved in the regulation of angiogenesis were anchored to oligo-ethylene glycol-capped gold nanoparticles (AuNPs) and used to evaluate the modulation of vascular development using an ex ovo chick chorioallantoic membrane assay. These nanoparticles alter the balance between naturally secreted pro- and antiangiogenic factors, under various biological conditions, without causing toxicity. Exposure of chorioallantoic membranes to AuNP–peptide activators of angiogenesis accelerated the formation of new arterioles when compared to scrambled peptide-coated nanoparticles. On the other hand, antiangiogenic AuNP–peptide conjugates were able to selectively inhibit angiogenesis in vivo. We demonstrated that AuNP vectorization is crucial for enhancing the effect of active peptides. Our data showed for the first time the effective control of activation or inhibition of blood vessel formation in chick embryo via AuNP-based formulations suitable for the selective modulation of angiogenesis, which is of paramount importance in applications where promotion of vascular growth is desirable (eg, wound healing) or ought to be contravened, as in cancer development. Keywords: angiogenesis activators, antiangiogenic, CAM assay, gold nanoparticles, peptide-coated gold nanoparticles, vascular development

Catarina Roma-Rodrigues,1 Alexandra R Fernandes1,2 1UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, Caparica, Portugal; 2Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal Abstract: Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems. Keywords: hypertrophic cardiomyopathy, molecular diagnosis, sarcomere, next-generation sequencing, sudden cardiac death

Isabel Fernandes,1,2 Teresa R Pacheco,2 Adília Costa,3 Ana C Santos,2 Ana R Fernandes,3 Mara Santos,3 António G Oliveira,4 Sandra Casimiro,2 António Quintela,1 Afonso Fernandes,2 Madalena Ramos,3 Luís Costa1,21Department of Medical Oncology, Hospital Santa Maria, CHLN, Lisboa, Portugal; 2Clinical and Translational Oncology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; 3Department of Pathology, Hospital Santa Maria, CHLN, Lisboa, Portugal; 4Department of Biostatistics, Faculdade de Ciências Médicas, Universidade Nova, Lisboa, PortugalIntroduction: Somatostatin analogs (SSAs) are used as part of standard treatment for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been suggested. Our purpose was to evaluate the activation status of the AKT/mTOR pathway in advanced metastatic NETs and identify biomarkers of response to SSA therapy.Patients and methods: Expression of phosphatase and tensin homolog (PTEN), phosphorylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinicopathological parameters and progression-free survival under treatment with SSAs.Results: A positive association between p-AKT and p-S6 expression was identified (P = 0.01) and higher expression of both markers was observed in pancreatic NETs. AKT/mTOR activation was observed without the loss of PTEN expression. Tumors showing AKT/mTOR signaling activation progressed faster when treated with SSAs: higher expression of p-AKT or p-S6 predicted a median progression-free survival of 1 month vs 26.5 months for lower expression (P = 0.02).Conclusion: Constitutive activation of the AKT/mTOR pathway was associated with shorter time-to-progression in patients undergoing treatment with SSAs. Larger case series are needed to validate whether p-AKT(Ser473) and p-S6(Ser240/244) can be used as prognostic markers of response to therapy with SSAs.Keywords: mTOR pathway, neuroendocrine tumor, somatostatin analogs

We propose a Mutual Language Policy to mediate shared interests between Chinese and indigenous workers in minimalizing frictions related to language attitudes, socio-cultural attitudes, ideologies and identities. So far, language policy has only sided with indigenous interests initiated by the government and has not involved foreign interests. By using multiple case study, we analyzed language attitudes, socio-cultural attitudes, as well as ideologies and identities of Chinese and indigenous workers to understand the frictions that occurred. We found that the language attitude of the Chinese workers was considered positive while the dominant use of Mandarin was only caused by the lack of mastery of both Indonesian and English. Next, the socio-cultural attitude of Chinese workers that seemed exclusive was basically caused by two main things,firstly, their concern about counterculture and contra behavior towards indigenous people.Secondly, the social class in employment context. Finally, the defense of the ideology and identity of the indigenous community seemed so strong was because of the collective defense system. Shared interests among them in a mutual language policy concept are also discussed.

This study aimed at obtaining information from neurolinguistic perspective about how children with mental retardation experience language learning by focusing on syntax device and unit disorder. With a qualitative paradigm, this study involved three children with mental retardation aged 17, 12, and 13 years at a special school in East Jakarta. Data in the form of utterances from three children with mental retardation through communication interactions were collected and produced 12 recordings which were then analyzed by apply-ing content analysis technique. The results of this study indicated that there were 151 errors in the form of syntax unit disorder, and the most errors were in the form of the phrase unit, amounting to 61 errors. In terms of syntax device disorder, 37 errors were found, of which the most errors were in intonation defects, amounting to 12 errors. The conclusion of the study is that children with mental retardation experience language disorders in the form of syntax defects because they are influenced by neurological disorders. How-ever, we see that these findings should not be standard benchmarks for mental and neurological disorders, so we argue that the defects in the syntax devices and units exhibited by children with mental retardation should be seen as a componential model of language issue on which their language development should be more focused on the meaning they get from information. In other words, we cannot just stick to the results which state that children with mental retardation have language difficulties but we must focus more on what they can understand as meaningful language to them. Therefore, we recommend trying to approach it with the concept of componential model of language that may be applicable with some technologies as innovative teaching and learning for teachers as well as progressive education for the children with mental retardation for their language learning experiences.

Speaking English skill has been trending in the mastery of foreign languages since the 19th century. However, at the beginning of the emergence of foreign language teaching in Indonesia, mastery of English speaking skills was only seen as an issue of formal learning outcomes in which English is a cumpolsory subject at the secondary school level. This condition led to the prestige of mastering English speaking skills starting to decline since the beginning of the 20th century where learning technology was increasingly sophisticated and brought formal learners of foreign languages on their own paths to master it. By using the Multiple Case Study, the issue that is the most underlying the students’ achievement of the English speaking skills mastery, how theylearnto achievethe skills, and how to keep on going on the skills were investigated. 10 informants were involved consisting of 7 active students and 3 alumni at and from UniversitasSembilanbelas November Kolaka, Southeast Sulawesi. Data were collected systematically through in-depth interviews, Focus Group Discussion (FGD), and documentation. Data were analyzed by applying six steps of Auerbach& Silverstein's analysis. The result revealed that a sense of liking was the most underlying issue in the informants’ achievement in English speaking skills, especially the past sense of liking. The result also revealed that the informants had a unique way in learning the English speaking skills, it was in an unpredictable way; they learned whenever and wherever they like, according to their own desire or willingness or pleasure, situational and curious – based, and free from formal regulations. Keywords: Sense Of Liking, English Speaking Skills, English As A Foreign Language, Preferent Learning

This research was conducted to analyze the differences between certified and non-certified English teachers in the teaching and learning process. The researcher formulated the objective of the research was to find out the differences between certified and non-certified English teachers in the teaching and learning process. Based on the objective of the research above, so the researcher came to analize the differences between certified and non-certified English teachers, they were one of certified English teacher in SMP Neg. 1 Kolaka and one of non-certified English teacher in SMK Negeri 1 Kolaka. The design of the research, the researcher used a descriptive qualitative analysis. In conducting the research, the researcher used two kinds of data collection, they were interview and observation. In analysis of the data, the researcher used techniques of data analysis by Miles and Huberman, namely data reduction, data display and verifying and conclusion. In representing the analysis, the researcher mentioned the findings of certified and non-certified English teachers in the teaching and learning process. Furthermore, through out, the analysis, the researcher explained that certified and non-certified English teachers had some differences in the teaching and learning process. They showed differences in some indicators, they were material mastery, systematic presentation, methods application, using media, performance and motivation. Based on the finding and analysis, the researcher made conclusion that certified English teacher didn’t have all indicators in his teaching and learning process. Conversely, non-certified English teacher had all indicators in his teaching and learning process. In other words, non-certified English teacher had good quality than certified English teacher.

Nos últimos anos tem-se observado aumento na prevalência da infecção pelo vírus da imunodeficiência humana entre mulheres brasileiras. O objetivo deste estudo foi o de determinar conhecimentos, atitudes e práticas de prevenção com relação às doenças de transmissão sexual (DST) no que se refere a mulheres atendidas na rede primária de saúde de Campinas, São Paulo, para implementar futuras ações. Entre 249 mulheres entrevistadas, 10% disseram usar a camisinha e 7,6% relataram uso consistente. Apesar de a maioria das mulheres (87,6%) referir a televisão como fonte de informação, a qualidade desta foi pobre para sensibilizá-las do risco das DST. A totalidade das mulheres expressou confiança no médico. Concluiu-se que as mulheres não optam pelo uso da camisinha para prevenção de DST/AIDS, utilizando-o, em geral, com a intenção de contracepção. É preciso implementar a adoção do diálogo informativo a respeito das DST/AIDS durante a consulta e inovar a forma e a qualidade das informações, de modo a viabilizar maior aderência da população às práticas do comportamento sexual seguro.

Abstract Background Selenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive. Methods In this paper, we investigate the apoptosis signalling mechanisms in sarcomatoid and epithelioid mesothelioma cells after selenite treatment. Apoptosis was measured with the Annexin-PI assay. The mitochondrial membrane potential, the expression of Bax, Bcl-XL, and the activation of caspase-3 were assayed with flow cytometry and a cytokeratin 18 cleavage assay. Signalling through JNK, p38, p53, and cathepsins B, D, and E was investigated with chemical inhibitors. Furthermore, the expression, nuclear translocation and DNA-binding activity of p53 was investigated using ICC, EMSA and the monitoring of p21 expression as a downstream event. Levels of thioredoxin (Trx) were measured by ELISA. Results In both cell lines, 10 μM selenite caused apoptosis and a marked loss of mitochondrial membrane potential. Bax was up-regulated only in the sarcomatoid cell line, while the epithelioid cell line down-regulated Bcl-XL and showed greater caspase-3 activation. Nuclear translocation of p53 was seen in both cell lines, but very little p21 expression was induced. Chemical inhibition of p53 did not protect the cells from apoptosis. p53 lost its DNA binding ability after selenite treatment and was enriched in an inactive form. Levels of thioredoxin decreased after selenite treatment. Chemical inhibition of MAP kinases and cathepsins showed that p38 and cathepsin B had some mediatory effect while JNK had an anti-apoptotic role. Conclusion We delineate pathways of apoptosis signalling in response to selenite, showing differences between epithelioid and sarcomatoid mesothelioma cells. These differences may partly explain why sarcomatoid cells are more sensitive to selenite.

Abstract Background The aim of this study was to evaluate bone mineral density (BMD) at baseline and at 18 and 36 months of use of etonogestrel (ENG)-and levonorgestrel (LNG)-releasing contraceptive implants. This is a continuation of a previous study in which BMD was evaluated at baseline and at 18 months of use. Methods A total of 111 women, 19–43 years of age, wererandomly allocated to use one of the two implants. At 36 months of follow-up, only 36 and 39 women were still using the ENG- and LNG-releasing implants, respectively. BMD was evaluated at the distal and at the ultra-distal radius of the non-dominant forearm using dual-energy X-ray absorptiometry. Results There was no difference in the BMD of users of either implant at 18 and at 36 months. BMD was significantly lower at 18 and at 36 months at the distal radius in both groups of users compared to pre-insertion values; however, no difference was found at the ultra-distal radius. Conclusion Women 19–43 years of age using either one of these two contraceptive implants for 36 months had lower BMD values at the distal radius compared to pre-insertion values; however, no difference was found at the ultra-distal radius.

In this work, we report the disruptive use of membrane-localized magnetic hyperthermia to promote the internalization of cell-impermeant probes. Under an alternating magnetic field, magnetic nanoparticles (MNPs) immobilized on the cell membrane via bioorthogonal click chemistry act as nanoheaters and lead to the thermal disruption of the plasma membrane, which can be used for internalization of different types of molecules, such as small fluorescent probes and nucleic acids. Noteworthily, no cell death, oxidative stress and alterations of the cell cycle are detected after the thermal stimulus, although cells are able to sense and respond to the thermal stimulus through the expression of different types of heat shock proteins (HSPs). Finally, we demonstrate the utility of this approach for the transfection of cells with a small interference RNA (siRNA), revealing a similar efficacy to a standard transfection method based on the use of cationic lipid-based reagents (such as Lipofectamine), but with lower cell toxicity. These results open the possibility of developing new procedures for "opening and closing" cellular membranes with minimal disturbance of cellular integrity. This on-demand modification of cell membrane permeability could allow the direct intracellular delivery of biologically relevant (bio)molecules, drugs and nanomaterials, thus overcoming traditional endocytosis pathways and avoiding endosomal entrapment.

The rise of antibiotic-resistant bacterial strains has become a critical health concern. According to the World Health Organization, the market introduction of new antibiotics is alarmingly sparse, underscoring the need for novel therapeutic targets. The LytR-CpsA-Psr (LCP) family of proteins, which facilitate the insertion of cell wall glycopolymers (CWGPs) like teichoic acids into peptidoglycan, has emerged as a promising target for antibiotic development. LCP proteins are crucial in bacterial adhesion and biofilm formation, making them attractive for disrupting these processes. This study investigated the structural and functional characteristics of the LCP domain of LytR from Streptococcus dysgalactiae subsp. dysgalactiae. The protein structure was solved by X-ray Crystallography at 2.80 Å resolution. Small-angle X-ray scattering (SAXS) data were collected to examine potential conformational differences between the free and ligand-bound forms of the LytR LCP domain. Additionally, docking and molecular dynamics (MD) simulations were used to predict the interactions and conversion of ATP to ADP and AMP. Experimental validation of these predictions was performed using malachite green activity assays. The determined structure of the LCP domain revealed a fold highly similar to those of homologous proteins while SAXS data indicated potential conformational differences between the ligand-free and ligand-bound forms, suggesting a more compact conformation during catalysis, upon ligand binding. Docking and MD simulations predicted that the LytR LCP domain could interact with ADP and ATP and catalyze their conversion to AMP. These predictions were experimentally validated by malachite green activity assays, confirming the protein's functional versatility. The study provides significant insights into the structural features and functional capabilities of the LCP domain of LytR from S. dysgalactiae subsp. dysgalactiae. These findings pave the way for designing targeted therapies against antibiotic-resistant bacteria and offer strategies to disrupt bacterial biofilm formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paquete-Ferreira, Freire, Fernandes, Muthukumaran, Ramos, Bryton, Panjkovich, Svergun, Santos, Correia, Fernandes, Romão, Sousa and Santos-Silva.)

Lung cancer (LC) is a leading cause of global cancer-related deaths, highlighting the development of innovative methods for biomarker detection improving the early diagnostics. microRNAs (miRs) alterations are known to be involved in the initiation and progression of human cancers and can act as biomarkers for diagnostics and treatment. Herein, we develop the application of molecular beacon (MB) technology to monitor miR-155-3p expression in human lung adenocarcinoma A549 cells without complementary DNA synthesis, amplification, or expensive reagents. Furthermore, we produced gold nanoparticles (AuNPs) for delivering antisense oligonucleotides into A549 cells to reduce miR-155-3p expression, which was subsequently detectable using the MB. The MB was designed and structural characterized by Förster Resonance Energy Transfer (FRET)-melting, Circular Dichroism (CD), Nuclear magnetic resonance (NMR), and fluorometric experiments, and then the hybridization conditions were optimized for an in vitro approach involving the detection of miR-155-3p in total RNA extracted from A549 cell line. The expression profile of miR-155-3p was obtained by RT-qPCR. The results demonstrated that MB was properly designed and showed efficacy in targeting miR-155-3p. Furthermore, a limit of detection down to nanomolar concentration was achieved and the specificity of the biosensor was proved. Moreover, the self-assembly of ASOs with AuNPs exhibited exceptional target specificity, effectively silencing miR-155-3p. Notably, compared to lipid-based transfection agent, AuNPs displayed superior silencing efficiency. We highlighted the ability of MB to detect changes in the target gene expression after gene silencing. Overall, this innovative approach represents a promising tool for detecting various biomarkers at the same time, with potential applications in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3a-d) and N-methyl-N-benzylamine (azaindoles 4a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4b and 4c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives., (© 2024 Wiley‐VCH GmbH.)

Artisanal mining is intensely carried out in developing countries, including Brazil and especially in the Amazon. This method of mineral exploration generally does not employ mitigation techniques for potential damages and can lead to various environmental problems and risks to human health. The objectives of this study were to quantify the concentrations of rare earth elements (REEs) and estimate the environmental and human health risks in cassiterite and monazite artisanal mining areas in the southeastern Amazon, as well as to understand the dynamics of this risk over time after exploitation. A total of 35 samples of wastes classified as overburden and tailings in active areas, as well as in areas deactivated for one and ten years were collected. Samples were also collected in a forest area considered as a reference site. The concentrations of REEs were quantified using alkaline fusion and ICP-MS. The results were used to calculate pollution indices and environmental and human health risks. REEs showed higher concentrations in anthropized areas. Pollution and environmental risk levels were higher in areas deactivated for one year, with considerable contamination factors for Gd and Sm and significant to extreme enrichment factors for Sc. Human health risks were low (< 1) in all studied areas. The results indicate that artisanal mining of cassiterite and monazite has the potential to promote contamination and enrichment by REEs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Eight 2,2':6',2″-terpyridines, substituted at the 4'-position with aromatic groups featuring variations in π-conjugation, ring size, heteroatoms, and methoxy groups, were employed to enhance the antiproliferative potential of [Cu 2 Cl 2 (R-terpy) 2 ](PF 6 ) 2 . Assessing the cytotoxicity in A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), and HCT116DoxR (colorectal carcinoma resistant to doxorubicin) and normal primary fibroblasts revealed that Cu(II) complexes with 4-quinolinyl, 4-methoxy-1-naphthyl, 2-furanyl, and 2-pyridynyl substituents showed superior therapeutic potential in HCT116DoxR cells with significantly reduced cytotoxicity in normal fibroblasts (42-129× lower). Besides their cytotoxicity, the Cu(II) complexes are able to increase intracellular ROS and interfere with cell cycle progression, leading to cell death by apoptosis and autophagy. Importantly, they demonstrated antimetastatic and antiangiogenic properties without in vivo toxicity. In accordance with their nuclear accumulation, the Cu(II) complexes are able to cleave pDNA and interact with bovine serum albumin, which is a good indication of their ability for internalization and transport toward tumor cells.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

The increasing and diversified use of rare earth elements (REE) is considered a potential source of pollution of environmental media including soils. This work documents critically overview data on the occurrence of REE in the fruiting bodies of wild and farmed species of edible and medicinal mushrooms, as this was identified as the largest published dataset of REE occurrence in foodstuff. Most of the literature reported occurrences of cerium (Ce) and lanthanum (La), but a number of studies lacked data on all lanthanides. The Ce, La, and summed REE occurrences were assessed through the criteria of environmental geochemistry, analytical chemistry, food toxicology, mushroom systematics, and ecology. Ce and La accumulate similarly in fruiting bodies and are not fractionated during uptake, maintaining the occurrence patterns of their growing substrates. Similarly, there is no credible evidence of variable REE uptake because the evaluated species data show natural, unfractionated patterns in accordance with the Oddo-Harkins' order of environmental lanthanide occurrence. Thus, lithosphere occurrence patterns of Ce and La as the first and the third most abundant lanthanides are reflected in wild and farmed mushrooms regardless of substrate and show that Ce is around twice more abundant than La. The current state of knowledge provides no evidence that mushroom consumption at these REE occurrence levels poses a health risk either by themselves or when included with other dietary exposure. Macromycetes appear to bio-exclude lanthanides because independently reported bioconcentration factors for different species and collection sites, typically range from < 1 to 0.001. This is reflected in fruiting body concentrations which are four to two orders of magnitude lower than growing substrates. KEY POINTS: •Original REE occurrence patterns in soils/substrates are reflected in mushrooms •No evidence for the fractionation of REE during uptake by fungi •Mushrooms bio-exclude REE in fruiting bodies., (© 2024. The Author(s).)

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Three-dimensional (3D) cell culture using tumor spheroids provides a crucial platform for replicating tissue microenvironments. However, effective gene modulation via nanoparticle-based transfection remains a challenge, often facing delivery hurdles. Gold nanoparticles (AuNPs) with their tailored synthesis and biocompatibility, have shown promising results in two-dimensional (2D) cultures, nevertheless, they still require a comprehensive evaluation before they can reach its full potential on 3D models. While 2D cultures offer simplicity and affordability, they lack physiological fidelity. In contrast, 3D spheroids better capture in vivo conditions, enabling the study of cell interactions and nutrient distribution. These models are essential for investigating cancer behavior, drug responses, and developmental processes. Nevertheless, transitioning from 2D to 3D models demands an understanding of altered internalization mechanisms and microenvironmental influences. This study assessed ASO-AuNP conjugates for silencing the c-MYC oncogene in 2D cultures and 3D tumor spheroids, revealing distinctions in gene silencing efficiency and highlighting the microenvironment's impact on AuNP-mediated gene modulation. Herein, we demonstrate that increasing the number of AuNPs per cell by 2.6 times, when transitioning from a 2D cell model to a 3D spheroid, allows to attain similar silencing efficiencies. Such insights advance the development of targeted gene therapies within intricate tissue-like contexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Oliveira, Fernandes and Baptista.)

Our aims were to evaluate changes in body characteristics, milk yield and milk constituents as well as to determine the relationship between the thermal environment and production characteristics during the first lactation of dairy Gyr cows managed on pasture. Between 2013 and 2015, forty-five primiparous dairy Gyr cows were evaluated from prepartum to 10 months of lactation in Southeast of Brazil. Body weight, body condition score (BCS), subcutaneous fat thickness (SFT), milk yield (305 d), and milk constituents were collected monthly and progesterone was collected weekly. Additionally, we determined the temperature humidity index (THI) based on microclimate data. Overall, the cows lost body weight until six months of lactation and there was a progressive decrease in BCS, SFT, milk yield and milk lactose as the months in lactation progressed. In contrast, there was an increase in milk fat, milk protein and milk solids. The thermal environment did not pose a consistent heat challenge, nevertheless, we found a positive correlation between the average THI two days before milk collection with milk yield, fat and lactose contents, but in contrast a negative correlation was found with total solids and protein. In conclusion, the THI and months of lactation affected the yield and constituents of milk. However, more studies are necessary to understand the impacts of body characteristics and thermal environment on yield and milk constituents throughout the productive life of Gyr dairy cows.

Aggregation prone molecules, such as tau, form both historically well characterized fibrillar deposits (neurofibrillary tangles) and recently identified phosphate-buffered saline (PBS) extract species called proteopathic seeds. Both can cause normal endogenous tau to undergo templated misfolding. The relationship of these seeds to the fibrils that define tau-related diseases is unknown. We characterized the aqueous extractable and sarkosyl insoluble fibrillar tau species derived from human Alzheimer brain using mass spectrometry and in vitro bioassays. Post-translational modifications (PTMs) including phosphorylation, acetylation and ubiquitination are identified in both preparations. PBS extract seed competent tau can be distinguished from sarkosyl insoluble tau by the presence of overlapping, but less abundant, PTMs and an absence of some PTMs unique to the latter. The presence of ubiquitin and other PTMs on the PBS-extracted tau species correlates with the amount of tau in the seed competent size exclusion fractions, with the bioactivity and with the aggressiveness of clinical disease. These results demonstrate that the PTMs present on bioactive, seed competent PBS extract tau species are closely related to, but distinct from, the PTMs of mature paired helical filaments, consistent with the idea that they are a forme fruste of tau species that ultimately form fibrils., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The research on tumor microenvironment (TME) has recently been gaining attention due to its important role in tumor growth, progression, and response to therapy. Because of this, the development of three-dimensional cancer models that mimic the interactions in the TME and the tumor structure and complexity is of great relevance to cancer research and drug development. Methods: This study aimed to characterize colorectal cancer spheroids overtime and assess how the susceptibility or resistance to doxorubicin (Dox) or the inclusion of fibroblasts in heterotypic spheroids influence and modulate their secretory activity, namely the release of extracellular vesicles (EVs), and the response to Dox-mediated chemotherapy. Different characteristics were assessed over time, namely spheroid growth, viability, presence of hypoxia, expression of hypoxia and inflammation-associated genes and proteins. Due to the importance of EVs in biomarker discovery with impact on early diagnostics, prognostics and response to treatment, proteomic profiling of the EVs released by the different 3D spheroid models was also assessed. Response to treatment was also monitored by assessing Dox internalization and its effects on the different 3D spheroid structures and on the cell viability. Results and Discussion: The results show that distinct features are affected by both Dox resistance and the presence of fibroblasts. Fibroblasts can stabilize spheroid models, through the modulation of their growth, viability, hypoxia and inflammation levels, as well as the expressions of its associated transcripts/proteins, and promotes alterations in the protein profile exhibit by EVs. Summarily, fibroblasts can increase cell-cell and cell-extracellular matrix interactions, making the heterotypic spheroids a great model to study TME and understand TME role in chemotherapies resistance. Dox resistance induction is shown to influence the internalization of Dox, especially in homotypic spheroids, and it is also shown to influence cell viability and consequently the chemoresistance of those spheroids when exposed to Dox. Taken together these results highlight the importance of finding and characterizing different 3D models resembling more closely the in vivo interactions of tumors with their microenvironment as well as modulating drug resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2023 Valente, Cordeiro, Luz, Melo, Rodrigues, Baptista and Fernandes.)

Background: Antimicrobial resistance is one of the most pressing health issues of our time. The increase in the number of antibiotic-resistant bacteria allied to the lack of new antibiotics has contributed to the current crisis. It has been predicted that if this situation is not dealt with, we will be facing 10 million deaths due to multidrug resistant infections per year by 2050, surpassing cancer-related deaths. This alarming scenario has refocused attention into researching alternative drugs to treat multidrug-resistant infections., Aims: In this study, the antimicrobial activities of four manganese complexes containing 1,2,3,-triazole and clotrimazole ligands have been evaluated. It is known that azole antibiotics coordinated to manganese tricarbonyl complexes display interesting antimicrobial activities against several microbes. In this work, the effect of the introduction of 1,2,3,-triazole-derived ligands in the [Mn(CO) 3 (clotrimazole)] fragment has been investigated against one Gram-positive bacterium and five Gram-negative bacteria., Methods: The initial antimicrobial activity of the above-mentioned complexes was assessed by determining the minimum inhibitory and bactericidal concentrations using the broth microdilution method. Growth curves in the presence and absence of the complexes were performed to determine the effects of these complexes on the growth of the selected bacteria. A possible impact on cellular viability was determined by conducting the MTS assay on human monocytes., Results: Three of the Mn complexes investigated ( 4 - 6 ) had good antimicrobial activities against all the bacteria tested, with values ranging from 1.79 to 61.95 µM with minimal toxicity., Conclusions: Due to the increased problem of antibiotic resistance and a lack of new antibacterial drugs with no toxicity, these results are exciting and show that these types of complexes can be an avenue to pursue in the future.

Rudimentary methods are used to exploit gold (Au) in several artisanal mines in the Amazon, producing hazardous wastes that may pose risks of contamination by rare earth elements (REEs). The objectives of this study were to quantify the concentrations of REEs and assess their environmental and human health risks in artisanal Au mining areas in the northeastern Amazon. Thus, 25 samples of soils and mining wastes were collected in underground, colluvial, and cyanidation exploration sites, as well as in a natural forest that was considered as a reference area. The concentrations of REEs were quantified using alkaline fusion and inductively coupled plasma mass spectrometry, and the results were used to estimate pollution indices and risks associated with the contaminants. All REEs showed higher concentrations in waste deposition areas than in the reference area, especially Ce, Sc, Nd, La, Pr, Sm, and Eu. Pollution and enrichment levels were higher in the underground and cyanidation mining areas, with very high contamination factors (6.2-27) for Ce, Eu, La, Nd, Pr, Sm, and Sc, and significant to very high enrichment factors (5.5-20) for Ce, La, Nd, Pr, and Sc. The ecological risk indices varied from moderate (167.3) to high (365.7) in the most polluted sites, but risks to human health were low in all areas studied. The results of this study indicate that artisanal Au mining has the potential to cause contamination, enrichment, and ecological risks by REEs in the northeastern Amazon. Mitigation measures should be implemented to protect the environment from the negative impacts of these contaminants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Some types of poultry bedding made from recycled materials have been reported to contain environmental contaminants such as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, dioxins), polychlorinated biphenyls (PCBs) brominated flame retardants (BFRs) polychlorinated naphthalenes (PCNs), polybrominated dioxins (PBDD/Fs), perfluoroalkyl substances (PFAS), etc. In one of the first studies of its kind, the uptake of these contaminants by chicken muscle tissue, liver, and eggs from three types of recycled, commercially available bedding material was simultaneously investigated using conventional husbandry to raise day old chickens to maturity. A weight of evidence analysis showed that PCBs, polybrominated diphenylethers (PBDEs), PCDD/Fs, PCNs and PFAS displayed the highest potential for uptake which varied depending on the type of bedding material used. During the first three to four months of laying, an increasing trend was observed in the concentrations of ΣTEQ (summed toxic equivalence of PCDD/Fs, PCBs, PBDD/Fs, PCNs and polybrominated biphenyls), NDL-PCBs and PBDEs in the eggs of chickens raised on shredded cardboard. Further analysis using bio-transfer factors (BTFs) when egg production reached a steady state, revealed that some PCB congeners (PCBs 28, 81, 138, 153 and 180) irrespective of molecular configuration or chlorine number, showed the highest tendency for uptake. Conversely, BTFs for PBDEs showed good correlation with bromine number, increasing to a maximum value for BDE-209. This relationship was reversed for PCDFs (and to some extent for PCDDs) with tetra- and penta- chlorinated congeners showing a greater tendency for selective uptake. The overall patterns were consistent, although some variability in BTF values was observed between tested materials which may relate to differences in bioavailability. The results indicate a potentially overlooked source of food chain contamination as other livestock products (cow's milk, lamb, beef, duck, etc.) could be similarly impacted., Competing Interests: Declaration of competing interest The authors assert that they have no conflict of interest (financial or non-financial) in the subject matter discussed in this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Soil conditioner is class of products used to enhance physics, physicochemical or soil biological activities, being able to recover disturbed or nutritional unbalanced soils. The formulation of a soil conditioner composed by bauxite residue (BR), and organic oil palm wastes, as raw materials, was recently proposed as an innovative strategy for the Brazilian acid soils amendment. Here we show the results of soil conditioner amended soil leaching tests and agronomical performance. The soil conditioners were formulated by BR mixed with decomposed POC (palm oil compost) and non-decomposed POMW (palm oil mill waste) oil palm wastes, in the proportion of 25% BR + 75% POC (T1) and 50% BR + 50% POMW (T2), in addition to the treatment with 100% POMW without BR (T3) and limestone at a dose calculated to raise soil pH to 6.0 (T4). Except for T4, all conditioners were applied to the soil at doses of 40, 80, and 120 t ha -1 for leaching tests. The experimental plots were composed of polyvinyl chloride columns, filled with 5 kg of soil, with bottles adapted with hoses at the bottom to facilitate drainage of the leachate. After leaching tests, the respective columns were used as pots for the cultivation of Brachiaria grass, stage with addition of a control composed by undisturbed soil (T5). The pH of the leachates had changes, but the use of BR associated with POMW was similar to the use of limestone. Of the 65 chemical elements evaluated, only nine were identified in the leachate, being most of them considered as plant nutrients. As for soil pH, limestone was slightly higher (6.6) than treatments that had BR (5.5). Brachiaria grass cultivated in the soil amended with conditioners showed similar results of limestone treated soil for the parameters of plant development and showed fertility improvement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: To minimize environmental colonization by microorganisms that may persist and thrive in healthcare settings, thus reducing healthcare-associated infections (HAIs), new insights over already known biocides are certainly of relevance. Although the efficacy of hydrogen peroxide (H 2 O 2 ) against the emergent yeast Candida auris is moderately documented, concerns over the potential induction of resistance after repeated exposure do persist. The main objective of the present study was to evaluate the hypothetical induction of Candida auris resistance following 30 days of consecutive exposure to lethal and sublethal concentrations of H 2 O 2 . Furthermore, the authors aimed to elucidate about the rank of efficacy of H 2 O 2 against C. auris comparing to other Candida species and whether different strains of C. auris may display different susceptibilities to H 2 O 2 ., Methods: During the induction of resistance assays, both type strains and clinical isolates of Candida auris, Candida albicans and Candida parapsilosis were exposed repeatedly to defined concentrations of H 2 O 2 , for 30 days., Results: After that period, no significant differences were found when comparing the minimal inhibitory concentration values of H 2 O 2 in case of the induced strains versus each respective positive control. Moreover, H 2 O 2 displayed similar effectiveness against all the tested Candida species and no differences were demonstrated among the distinct strains of C. auris., Conclusions: The adoption of H 2 O 2 solutions in routine protocols in order to promote disinfection standards against Candida auris, improving patient safety and reducing healthcare costs, is certainly welcomed., (© 2023. BioMed Central Ltd., part of Springer Nature.)

This review updates information on the historical manufacture and unintentional production of polychlorinated naphthalenes (PCNs). The direct toxicity of PCNs as a result of occupational human exposure and through contaminated feed in livestock was recognised decades ago, making PCNs a precursor chemical for consideration in occupational medicine and occupational safety. This was confirmed by the listing of PCNs by the Stockholm Convention as a persistent organic pollutant in the environment, food, animals and humans. PCNs were manufactured globally between 1910 ∼ 1980, but reliable data on the volumes produced or national outputs are scarce. A total figure for global production would be useful for the purposes of inventory and control and it is clear that combustion related sources such as waste incineration, industrial metallurgy and use of chlorine are current major sources of PCNs to the environment. The upper bound estimate of total global production has been put at 400,000 metric tons but the amounts (at least, many 10 s of tonnes) that are currently emitted unintentionally every year through industrial combustion processes should also be inventoried along with estimates for emissions from bush and forest fires. This would however require considerable national effort, financing and co-operation from source operators. The historical (1910-1970 s) production and resulting emissions through diffusive/evaporative releases through usage, are still reflected in documented occurrence and patterns of PCNs in human milk in Europe and other locations worldwide. More recently, PCN occurrence in human milk from Chinese provinces has been linked to local unintentional emissions from thermal processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The rising demand for minimally processed, natural, and healthier food products has led to the search for alternative and multifunctional bioactive food components. Therefore, the present study focuses on the functional proprieties of a peptide fraction derived from Saccharomyces cerevisiae metabolism. The antimicrobial activity of the peptide fraction is evaluated against various foodborne pathogens, including Candida albicans , Candida krusei , Escherichia coli , Listeria monocytogenes , and Salmonella sp. The peptide fraction antioxidant properties are assessed using FRAP and DPPH scavenging capacity assays. Furthermore, the peptide fraction's cytotoxicity is evaluated in colorectal carcinoma and normal colon epithelial cells while its potential as an antidiabetic agent is investigated through α-amylase and α-glucosidase inhibitory assays. The results demonstrate that the 2-10 kDa peptide fraction exhibits antimicrobial effects against all tested microorganisms, except C. krusei . The minimal inhibitory concentration for E. coli , L. monocytogenes , and Salmonella sp. remains consistently low, at 0.25 mg/mL, while C. albicans requires a higher concentration of 1.0 mg/mL. Furthermore, the peptide fraction displays antioxidant activity, as evidenced by DPPH radical scavenging activity of 81.03%, and FRAP values of 1042.50 ± 32.5 µM TE/mL at 1.0 mg/mL. The peptide fraction exhibits no cytotoxicity in both tumor and non-tumoral human cells at a concentration up to 0.3 mg/mL. Moreover, the peptide fraction presents anti-inflammatory activity, significantly reducing the expression of the TNFα gene by more than 29.7% in non-stimulated colon cells and by 50% in lipopolysaccharide-stimulated colon cells. It also inhibits the activity of the carbohydrate digestive enzymes α-amylase (IC 50 of 199.3 ± 0.9 µg/mL) and α-glucosidase (IC 20 of 270.6 ± 6.0 µg/mL). Overall, the findings showed that the peptide fraction exhibits antibacterial, antioxidant, anti-inflammatory, and antidiabetic activity. This study represents a step forward in the evaluation of the functional biological properties of S. cerevisiae bioactive peptides.

Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.

Aim: In order to avoid side effects of lithium doses in some patients, some commonly cultivated mushroom species including A. bisporus have been successfully lithiated, with the potential to provide more acceptable sources of Li. This study assessed the in vitro release (potential bioaccessibility) and possible intake of Li using the action of artificial gastrointestinal juices on lithiated and nonlithiated (control) button mushrooms (Agaricus bisporus) that were subjected to certain modes of culinary processing., Methods: In the in vitro release study, mushrooms were processed using a number of routinely used domestic treatments including rehydrating dried mushrooms, blanching and blanching followed by pickling of fresh or frozen mushrooms. The in vitro digestion procedure used artificial gastrointestinal juices in a two-stage methodology that was adapted from 'The Bioaccessibility Research Group of Europe' method. The Li concentrations were determined using an inductively coupled argon plasma-dynamic reactive cell-mass spectrometer., Results: Lithium was found to be more bioaccessible from caps of lithiated mushrooms compared with nonlithiated. Releases from the caps and stipes of blanched or blanched and then pickled mushrooms through gastric digestion ranged from 32 ± 2 to 50 ± 1% relative to the dried product and was lower for gastrointestinal digestion, which ranged from 16 ± 1 to 20 ± 1%., Conclusion: Losses of Li sustained through blanching or blanching followed by pickling of fresh mushrooms (41-87% wet weight) combined with limited accessibility during gastrointestinal release (16-55%) result in much lower bioavailability of the dose from lithiated products. A 300-g meal would provide <5% of the Li (6 mg) required for potential preventative treatments, such as reducing suicide rates and lowering dementia risk., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The ruthenium arene fragment is a rich source for the design of anticancer drugs; in this design, the co-ligand is a critical factor for obtaining effective anticancer complexes. In comparison with other types of ligands, N-heterocyclic carbenes (NHCs) have been less explored, despite the versatility in structural modifications and the marked stabilization of metal ions, being these characteristics important for the design of metal drugs. However, notable advances have been made in the development of NHC Ruthenium arene as anticancer agents. These advances include high antitumor activities, proven both in in vitro and in in vivo models and, in some cases, with marked selectivity against tumorigenic cells. The versatility of the structure has played a fundamental role, since they have allowed a selective interaction with their molecular targets through, for example, bio-conjugation with known anticancer molecules. For this reason, the structure-activity relationship of the imidazole, benzimidazole, and abnormal NHC ruthenium (II) η 6 -arene complexes have been studied. Taking into account this study, several synthetic aspects are provided to contribute to the next generations of this kind of complexes. Moreover, in recent years nanotechnology has provided innovative nanomedicines, where half-sandwich Ruthenium(II) complexes are paving their way. In this review, the recent developments in nanomaterials functionalized with Ruthenium complexes for targeted drug delivery to tumors will also be highlighted., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2023. Published by Elsevier Inc.)

The work is focused on anticancer properties of dipicolinate (dipic)-based vanadium(IV) complexes [VO(dipic)(N ∩ N)] bearing different diimines (2-(1 H -imidazol-2-yl)pyridine, 2-(2-pyridyl)benzimidazole, 1,10-phenanthroline-5,6-dione, 1,10-phenanthroline, and 2,2'-bipyridine), as well as differently 4,7-substituted 1,10-phenanthrolines. The antiproliferative effect of V(IV) systems was analyzed in different tumors (A2780, HCT116, and HCT116-DoxR) and normal (primary human dermal fibroblasts) cell lines, revealing a high cytotoxic effect of [VO(dipic)(N ∩ N)] with 4,7-dimethoxy-phen ( 5 ), 4,7-diphenyl-phen ( 6 ), and 1,10-phenanthroline ( 8 ) against HCT116-DoxR cells. The cytotoxicity differences between these complexes can be correlated with their different internalization by HCT116-DoxR cells. Worthy of note, these three complexes were found to (i) induce cell death through apoptosis and autophagy pathways, namely, through ROS production; (ii) not to be cytostatic; (iii) to interact with the BSA protein; (iv) do not promote tumor cell migration or a pro-angiogenic capability; (v) show a slight in vivo anti-angiogenic capability, and (vi) do not show in vivo toxicity in a chicken embryo.

FucoPol, a fucose-rich polyanionic polysaccharide, was used for the first time for the preparation of hydrogel membranes (HMs) using Fe 3+ as a crosslinking agent. This study evaluated the impact of Fe 3+ and FucoPol concentrations on the HMs' strength. The results show that, above 1.5 g/L, Fe 3+ concentration had a limited influence on the HMs' strength, and varying the FucoPol concentration had a more significant effect. Three different FucoPol concentrations (1.0, 1.75 and 2.5 wt.%) were combined with Fe 3+ (1.5 g/L), resulting in HMs with a water content above 97 wt.% and an Fe 3+ content up to 0.16 wt.%. HMs with lower FucoPol content exhibited a denser porous microstructure as the polymer concentration increased. Moreover, the low polymer content HM presented the highest swelling ratio (22.3 ± 1.8 g/g) and a lower hardness value (32.4 ± 5.8 kPa). However, improved mechanical properties (221.9 ± 10.2 kPa) along with a decrease in the swelling ratio (11.9 ± 1.6 g/g) were obtained for HMs with a higher polymer content. Furthermore, all HMs were non-cytotoxic and revealed anti-inflammatory activity. The incorporation of FucoPol as a structuring agent and bioactive ingredient in the development of HMs opens up new possibilities for its use in tissue engineering, drug delivery and wound care management.

The LQFM05 is a prototype drug designed for treatment of psychiatric disorders, such as schizophrenia, exhibiting anxiolytic- and antidepressant-like (12 or 24 µmol/kg) effects in classical behavioral tests. In order to evaluate its pharmacokinetic properties, a liquid chromatography method coupled to a quadrupole time of flight mass spectrometry system (LC-QTOF/MS) was developed and fully validated for LQFM05 analysis in rat plasma and tissue samples (brain, heart, liver, and kidneys). Liquid-liquid extraction, solid phase extraction and protein precipitation were assessed as clean-up procedures for biological samples and analyte enrichment. Plasma and tissue samples underwent protein precipitation as a preliminary step, using acetonitrile. Linearity was fully demonstrated for the dynamic range (10.0 to 900.0 ng/mL), with r 2 values higher than 0.99 (RSD slope ≤ 2%, F cal < F tab , C cal < C tab ). Biodistribution studies in rats revealed high brain tissue concentrations (12.4 µg/g), suggesting elevated drug affinity to the main therapeutic target tissue, showing a blood partition coefficient of 1.9. Kidneys also showed great exposure and tissue affinity, suggesting a potential extrahepatic clearance. Likewise, all examined tissues exhibited satisfactory LQFMF05 distribution. The mass fragmentation spectrum indicated the presence of its main metabolite, LQFM235, yielded by high hepatic hydroxylation route, an equally bioactive derivative. Lastly, the developed LC-QTOF/MS method was shown to be sensitive (LOQ = 10 ng/mL), precise and accurate for LQFM05 determination in tissue homogenates and plasma samples.

Wired neurons form new presynaptic boutons in response to increased synaptic activity, however the mechanism(s) by which this occurs remains uncertain. Drosophila motor neurons (MNs) have clearly discernible boutons that display robust structural plasticity, being therefore an ideal system in which to study activity-dependent bouton genesis. Here, we show that in response to depolarization and in resting conditions, MNs form new boutons by membrane blebbing, a pressure-driven mechanism that occurs in 3-D cell migration, but to our knowledge not previously described to occur in neurons. Accordingly, F-actin is decreased in boutons during outgrowth, and non-muscle myosin-II is dynamically recruited to newly formed boutons. Furthermore, muscle contraction plays a mechanical role, which we hypothesize promotes bouton addition by increasing MN confinement. Overall, we identified a mechanism by which established circuits form new boutons allowing their structural expansion and plasticity, using trans-synaptic physical forces as the main driving force., (© 2023. The Author(s).)