Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis.

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.

Evolutionary Profile of Mayaro Virus in the Americas: An Update into Genome Variability.

The Mayaro virus (MAYV) is an arbovirus with emerging potential, though with a limited understanding of its epidemiology and evolution due to the lack of studies and surveillance. Here, we investigated 71 MAYV genome sequences from the Americas available at GenBank and characterized the phylogenetic relationship among virus strains. A phylogenetic analysis showed that sequences were grouped according to the genotypes L, D, and N. Genotype D sequences were closely related to sequences collected in adjacent years and from their respective countries, suggesting that isolates may have originated from circulating lineages. The coalescent analysis demonstrated similar results, indicating the continuous circulation of the virus between countries as well. An unidentified sequence from the USA was grouped with genotype D, suggesting the insertion of this genotype in the country. Furthermore, the recombination analysis detected homologous and three heterologous hybrids which presented an insertion into the nsP3 protein. Amino acid substitutions among sequences indicated selective pressure sites, suggesting viral adaptability. This also impacted the binding affinity between the E1-E2 protein complex and the Mxra8 receptor, associated with MAYV entry into human cells. These results provide information for a better understanding of genotypes circulating in the Americas.

Influence of diimine bidentate ligand in the nitrosyl and nitro terpyridine ruthenium complex on the HSA/DNA interaction and antiviral activity.

Nitric oxide (NO) acts in different physiological processes, such as blood pressure control, antiparasitic activities, neurotransmission, and antitumor action. Among the exogenous NO donors, ruthenium nitrosyl/nitro complexes are potential candidates for prodrugs, due to their physicochemical properties, such as thermal and physiological pH stability. In this work, we proposed the synthesis and physical characterization of the new nitro terpyridine ruthenium (II) complexes of the type [RuII(L)(NO2)(tpy)]PF6 where tpy = 2,2':6',2″-terpyridine; L = 3,4-diaminobenzoic acid (bdq) or o-phenylenediamine (bd) and evaluation of influence of diimine bidentate ligand NH.NHq-R (R = H or COOH) in the HSA/DNA interaction as well as antiviral activity. The interactions between HSA and new nitro complexes [RuII(L)(NO2)(tpy)]+ were evaluated. The Ka values for the HSA-[RuII(bdq)(NO2)(tpy)]+ is 10 times bigger than HSA-[RuII(bd)(NO2)(tpy)]+. The sites of interaction between HSA and the complexes via synchronous fluorescence suppression indicate that the [RuII(bdq)(NO2)(tpy)]+ is found close to the Trp-241 residue, while the [RuII(bd)(NO2)(tpy)]+ complex is close to Tyr residues. The interaction with fish sperm fs-DNA using direct spectrophotometric titration (Kb) and ethidium bromide replacement (KSV and Kapp) showed weak interaction in the system fs-DNA-[RuII(bdq)(NO)(tpy)]+. Furthermore, fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+ system showed higher intercalation constant. Circular dichroism spectra for fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+, suggest semi-intercalative accompanied by major groove binding interaction modes. The [RuII(bd)(NO2)(tpy)]+ and [RuII(bd)(NO)(tpy)]3+ inhibit replication of Zika and Chikungunya viruses based in the nitric oxide release under S-nitrosylation reaction with cysteine viral.

Exercise intensity governs tumor control in mice with breast cancer.

Introduction: Exercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity. Methods: We subjected mice to low intensity (Li), moderate intensity (Mi) or high intensity (Hi) exercise, or untrained control (Co) groups based on their individual maximal running capacity. Results: We found that exercise intensity played a critical role in tumor control. Only Mi exercise delayed tumor growth and reduced tumor burden, whereas Li or Hi exercise failed to exert similar antitumor effects. While both Li and Mi exercise normalized the tumor vasculature, only Mi exercise increased tumor infiltrated CD8+ T cells, that also displayed enhanced effector function (higher proliferation and expression of CD69, INFγ, GzmB). Moreover, exercise induced an intensity-dependent mobilization of CD8+ T cells into the bloodstream. Conclusion: These findings shed light on the intricate relationship between exercise intensity and cancer, with implications for personalized and optimal exercise prescriptions for tumor control.

Targeting of neuroblastoma cells through Kynurenine-AHR pathway inhibition.

Neuroblastoma poses significant challenges in clinical management. Despite its relatively low incidence, this malignancy contributes disproportionately to cancer-related childhood mortality. Tailoring treatments based on risk stratification, including MYCN oncogene amplification, remains crucial, yet high-risk cases often confront therapeutic resistance and relapse. Here, we explore the aryl hydrocarbon receptor (AHR), a versatile transcription factor implicated in diverse physiological functions such as xenobiotic response, immune modulation, and cell growth. Despite its varying roles in malignancies, AHR's involvement in neuroblastoma remains elusive. Our study investigates the interplay between AHR and its ligand kynurenine (Kyn) in neuroblastoma cells. Kyn is generated from tryptophan (Trp) by the activity of the enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). We found that neuroblastoma cells displayed sensitivity to the TDO2 inhibitor 680C91, exposing potential vulnerabilities. Furthermore, combining TDO2 inhibition with retinoic acid or irinotecan (two chemotherapeutic agents used to treat neuroblastoma patients) revealed synergistic effects in select cell lines. Importantly, clinical correlation analysis using patient data established a link between elevated expression of Kyn-AHR pathway genes and adverse prognosis, particularly in older children. These findings underscore the significance of the Kyn-AHR pathway in neuroblastoma progression, emphasizing its potential role as a therapeutic target.

Acridones as promising drug candidates against Oropouche virus.

Oropouche virus (OROV) is an emerging vector-borne arbovirus found in South America that causes Oropouche fever, a febrile infection similar to dengue fever. It has a high epidemic potential, causing illness in over 500,000 cases diagnosed since the virus was first discovered in 1955. Currently, the prevention of human viral infection depends on vaccination, but availability for many viruses is limited, and they are classified as neglected viruses. At present, there are no vaccines or antiviral treatments available. An alternative approach to limiting the spread of the virus is to selectively disrupt viral replication mechanisms. Here, we demonstrate the inhibitory effect of acridones, which efficiently inhibited viral replication by 99.9 % in vitro. To evaluate possible mechanisms of action, we conducted tests with dsRNA, an intermediate in virus replication, as well as MD simulations, docking, and binding free energy analysis. The results showed a strong interaction between FAC21 and the OROV endonuclease, which possibly limits the interaction of viral RNA with other proteins. Therefore, our results suggest a dual mechanism of antiviral action, possibly caused by ds-RNA intercalation. In summary, our findings demonstrate that a new generation of antiviral drugs could be developed based on the selective optimization of molecules.

Histological and immunohistochemical features of carcinomas with pulmonary involvement in cattle.

Primary pulmonary neoplasms in cattle are rare. There are few studies on the pathological findings of these neoplasms in this species. This study aimed to describe the histological and immunohistochemical findings of primary and metastatic pulmonary carcinomas in cattle. We conducted a retrospective study of 19 cases of epithelial neoplasms with pulmonary involvement. Histologically, most of the neoplasms were classified as primary pulmonary neoplasms, including different adenocarcinoma subtypes (4/19, 21%) and adenosquamous carcinomas (3/19, 16%), followed by squamous cell carcinoma (6/19, 32%), metastatic uterine adenocarcinoma (4/19, 21%), metastatic hepatocellular carcinoma (1/19, 5%), and metastatic cholangiocarcinoma (1/19, 5%). By immunohistochemistry, all neoplasms were positive for pancytokeratin, and 4/19 (21%) were positive for vimentin. Primary pulmonary neoplasms had immunoreactivity for thyroid transcription factor-1 (6/7), while only 2 of these cases were positive for napsin A. All cases with squamous differentiation (9/9) had immunoreactivity for cytokeratin (CK) 5/6, while only 7 of these cases were positive for p40. CK20, CK7, and CK8/18 showed varied immunoreactivity in the primary and metastatic pulmonary carcinomas but were important markers to confirm the diagnosis of primary mucinous adenocarcinoma and metastatic cholangiocarcinoma. HepPar-1 was only positive in the metastatic hepatocellular carcinoma. The limited number of cases of metastatic uterine adenocarcinomas in this study precluded identification of a specific immunophenotype for this tumor. Immunohistochemistry proved to be an important tool to confirm the proper classification of these neoplasms.

An outbreak of type C botulism in free-ranging Southern lapwing (Vanellus chilensis).

In the fall of 2021, a significant mortality event in free-ranging Southern Lapwing (Vanellus chilensis) occurred on a soccer field in southern Brazil. Approximately 130 adult southern lapwings died after showing weakness and flaccid paralysis, characterized by the inability to move or fly and drooped wings. Due to the large number of animals affected, there was concern that they had been criminally poisoned. The affected birds were found to have ingested maggots in fresh poultry litter incorporated into the grass surface. Postmortem examinations of four southern lapwings revealed no significant gross and histological findings. Polymerase Chain Reaction (PCR) for influenza A virus, flavivirus, and paramyxovirus was negative. Based on the epidemiological and clinical findings and the negative viral results, a presumptive diagnosis of botulism was made. This diagnosis was confirmed through mouse bioassay and seroneutralization, which detected botulinum toxin type C. Maggots loaded with botulinum neurotoxins were the probable vehicle for intoxication in the outbreak. Considering the impact of avian botulism on wild bird populations, our results may help prevent similar outbreaks in the future.

Novel Bidentate Amine Ligand and the Interplay between Pd(II) and Pt(II) Coordination and Biological Activity.

Pt(II) and Pd(II) coordinating N-donor ligands have been extensively studied as anticancer agents after the success of cisplatin. In this work, a novel bidentate N-donor ligand, the N-[[4-(phenylmethoxy)phenyl]methyl]-2-pyridinemethanamine, was designed to explore the antiparasitic, antiviral and antitumor activity of its Pt(II) and Pd(II) complexes. Chemical and spectroscopic characterization confirm the formation of [MLCl2 ] complexes, where M=Pt(II) and Pd(II). Single crystal X-ray diffraction confirmed a square-planar geometry for the Pd(II) complex. Spectroscopic characterization of the Pt(II) complex suggests a similar structure. 1 H NMR, 195 Pt NMR and HR-ESI-MS(+) analysis of DMSO solution of complexes indicated that both compounds exchange the chloride trans to the pyridine for a solvent molecule with different reaction rates. The ligand and the two complexes were tested for in vitro antitumoral, antileishmanial, and antiviral activity. The Pt(II) complex resulted in a GI50 of 10.5 µM against the NCI/ADR-RES (multidrug-resistant ovarian carcinoma) cell line. The ligand and the Pd(II) complex showed good anti-SARS-CoV-2 activity with around 65 % reduction in viral replication at a concentration of 50 µM.

Characterization of cutaneous lesions caused by natural tick infestation in cattle.

Although tick infestation is a significant health problem in livestock, there are limited studies on the dermatopathological aspects of natural tick infestation in cattle. This study aimed to describe the gross and histologic aspects of cutaneous lesions caused by tick infestation in cattle. Thirteen cases were selected based on necropsy data from a 10-year retrospective study. Predispositions were observed in beef cattle (P = .049) and the Angus breed (P = .012), and lesions occurred mainly in the fall (P = .007). Gross lesions included hypotrichosis (13/13; 100%), scales (12/13; 92%), alopecia (11/13; 85%), ulcers (7/13; 54%), crusts (7/13; 54%), and erosions (2/13; 15%). These gross lesions were mainly located in the thorax (12/13; 92%), head (11/13; 85%), abdomen (10/13; 77%), neck (9/13; 69%), limbs (9/13; 69%), and perineum (9/13; 69%). Histologically, all cases had ticks adhered to the epidermis with erosions (13/13; 100%), ulcers (11/13; 85%), orthokeratotic hyperkeratosis (13/13; 100%), irregular acanthosis (13/13; 100%), intraepidermal pustules (13/13; 100%), crusts (10/13; 77%), and ballooning degeneration (4/13; 31%). In the dermis, just below the tick insertion site, there was coagulation necrosis, fibrin deposition, and inflammatory infiltrate composed of mixed cells (neutrophils, lymphocytes, plasma cells, macrophages, and few eosinophils) (9/13; 69%), neutrophils (3/13; 23%), or eosinophils (1/13; 8%). This study reinforces the different patterns of cutaneous lesions caused by tick infestation in cattle, which should be considered as a potential cause of dermatitis in this species.

The Synthetic Peptide GA-Hecate and Its Analogs Inhibit Multiple Steps of the Chikungunya Virus Infection Cycle In Vitro.

Chikungunya virus (CHIKV) belongs to the Alphavirus genus and is responsible for significant outbreaks worldwide. Currently, there is no approved antiviral therapy against CHIKV. Bioactive peptides have great potential for new drug development. Here, we evaluated the antiviral activity of the synthetic peptide GA-Hecate and its analogs PSSct1905 and PSSct1910 against CHIKV infection. Initial screening showed that all three peptides inhibited the CHIKV replication cycle in baby hamster kidney fibroblast cells (BHK-21) and human hepatocarcinoma epithelial cells (Huh-7). GA-Hecate and its analog PSSct1905 were the most active, demonstrating suppression of viral infection by more than 91%. The analog PSSct1905 exhibited a protective effect in cells against CHIKV infection. We also observed that the analogs PSSct1905 and PSSct1910 affected CHIKV entry into both cell lines, inhibiting viral attachment and internalization. Finally, all tested compounds presented antiviral activity on the post-entry steps of CHIKV infection in all cells evaluated. In conclusion, this study highlights the potential of the peptide GA-Hecate and its analogs as novel anti-CHIKV compounds targeting different stages of the viral replication cycle, warranting the development of GA-Hecate-based compounds with broad antiviral activity.

L protein characterization and in silico screening of putative broad range target molecules for pathogenic mammarenaviruses from South America.

The genus Mammarenavirus belonging to the family Arenaviridae encompasses pathogenic viral species capable of triggering severe diseases in humans, causing concern for the health system due to the high fatality rate associated with them. Currently, there is a dearth of specific therapies against pathogens of the genus. Natural products isolated from plants have impacted the development of drugs against several diseases. The Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE) database offers several natural compounds with antimicrobial activities that can be used in the development of new antiviral drugs. In this context, here we modeled the arenavirus L protein, multifunctional machinery essential for the viral replicative cycle, making this enzyme a potential candidate for targeting the development of antivirals against genus pathogens. Using the modeled L protein, a virtual screening was performed, which suggested eleven molecules from the NuBBE database that binds to the active site of the L protein, which was promising in the in silico predictions of absorption and toxicity analysis. The NuBBE 1642 molecule proved to be the best candidate for four of the five species evaluated, acting as a possible broad-spectrum molecule. Additionally, our results showed that the L protein is highly conserved among species of the genus, as well as presenting close phylogenetic relationships between many of the species studied, strengthening its candidacy as a therapeutic target. The data presented here demonstrate that some NuBBE molecules are potential ligands for the L protein of arenaviruses, which may help to contain possible outbreaks.Communicated by Ramaswamy H. Sarma.

Insights into enterovirus a-71 antiviral development: from natural sources to synthetic nanoparticles.

Enteroviruses are pathogens responsible for several diseases, being enterovirus A71 (EVA71) the second leading cause of hand, foot, and mouth disease (HFMD), especially in Asia-Pacific countries. HFMD is mostly common in infants and children, with mild symptoms. However, the disease can result in severe nervous system disorders in children as well as in immunosuppressed adults. The virus is highly contagious, and its transmission occurs via fecal-oral, oropharyngeal secretions, and fomites. The EVA71 burdens the healthy systems and economies around the world, however, up to date, there is no antiviral approved to treat infected individuals and the existent vaccines are not available or approved to be used worldwide. In this context, an extensive literature research was conducted to describe and summarize the recent advances in natural and/or synthetic compounds with antiviral activity against EVA71. The summarized data presented here might simply encourage the future studies in EVA71 antiviral development, by encouraging further research encompassing these compounds or even the application of the techniques and technologies to improve or produce new antiviral molecules.

Spring water quality monitoring using multiple bioindicators from multiple collection sites.

The aim of this study was to examine the water quality of the Extrema River spring in a Brazilian Cerrado area. Three collection sites (P1 - P3) were sampled in the dry and rainy seasons, which are close to industries from different sectors. In the physicochemical analysis, a decrease in dissolved oxygen levels (<5 mg/L) and pH (< 6) at P3 was detected. An increase in heterotrophic bacteria count was recorded at all sites (> 500 colonies/ml). In ecotoxicological analyses, P2 and P3 exhibited toxicity using Vibrio fischeri (> 20%). In evaluating toxicity, the reduction in seed germination was significant utilizing Lactuca sativa at all locations and with Allium cepa only at P2; rootlet length was decreased at P3 on L. sativa and at all sites with A. cepa. In contrast, loss of membrane integrity and mitochondrial function of meristems was adversely affected at all locations using both L. sativa and A. cepa assays. Principal components analysis (PCA) approach indicated that seasonality apparently did not markedly interfere with the obtained data, but it is important to include more collection locations to be evaluated with multiple bioindicators in the spring region. Our data indicate the urgent need for more rigorous programs to monitor the discharge of effluents into water springs.

Green chemistry production of biopolymeric film-derived biomaterial prepared using natural alginate and vanillin compounds for application as a biocurative.

The present work presents the results obtained in the production of vanillin-doped alginate biopolymeric film using green chemistry methodology. Alginate dressings are already a therapeutic reality, but they act only by maintaining the appropriate environment for healing. In order to improve their properties, the incorporation of vanillin was proposed due to its antioxidant and antimicrobial potential. Different biopolymeric films were produced employing the experiment planning through response surface analysis, which allowed determining the best region for a medium value of solubility and high degree of swelling. This region refers to values above 0.07 g of CaCl2 and concentrations above 0.024 g of vanillin, triggering solubility between 25 and 30% and a degree of swelling above 100% and with fixed values of alginate (0.85 g). Such data are related to experiments (A), (B), and (C) listed in Table 1. Regarding the optimization of the process, the normal boundary intersection (NBI) method allowed the analysis of concave regions, predicting the optimal points and generating the Pareto chart with equidistant limits. The antimicrobial test allowed observing the antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa microorganisms from the biopolymeric films, as well as a solution of vanillin with calcium chloride and glycerol obtaining a halo of inhibition only in the presence of vanillin, and there was no significant difference between the results obtained in the experiments (A) and (B). The thermal analyses showed that the material has thermal stability in the ideal temperature range (~ 25 °C) for application as a biocurative. We preliminarily concluded that the alginate biopolymeric film doped with vanillin prepared using green chemical methodology presents antimicrobial properties and thermal stability that indicate its potential use as biocurative.

Anatomy and Histochemistry of the Vegetative System of Brachystele guayanensis (Lindl.) Schltr. (Orchidaceae), a Potential Medicinal Species.

The orchid genus Brachystele Schltr. (Orchidoideae, Cranichideae, Spiranthinae) comprises 20 species distributed from Mexico to Argentina, with 10 species found in Brazil. Anatomical studies of Orchidoideae Lindl. have been scarce, and the anatomy and histochemistry of Brachystele are still largely unknown. In this study, we conducted a characterization of the vegetative organs of B. guayanensis (Lindl.) Schltr. using standard anatomical and histochemical microtechniques. In this study, we provide the first information about the anatomy and histochemistry of Brachystele. The studied species was observed to display anatomical characters commonly found in the vegetative organs of representatives of the Cranichideae tribe (e.g., uniseriate epidermis; homogeneous mesophyll with 6-11 layers; rhizomes with rings of fibers; vascular bundles in the form of "^" or "v"; fleshy roots with uniseriate velamen, simple trichomes, and spiranthosomes). Others can be interpreted as adaptive strategies conditioned by the environment and their terrestrial life form (e.g., cuticle thickness; amphistomatic leaves; roots with reduced velamen compared to the cortex (18-20 layers); and raphides). In this study, cataphylls, and the presence of spiranthosomes in leaves, including stomatal guard cells, as well as alkaloids in these structures, are anatomically described for the first time in Orchidaceae. The presence of hyphae and pelotons in the stem of B. guayanensis is described for the first time in Cranichideae. Histochemical tests confirmed the presence of lignin, proteins, and alkaloids, the lipidic nature of the cuticle, starch grains stored in spiranthosomes, and the composition of the raphides. Alkaloids were observed in abundance, particularly in the roots, suggesting a potential role in defense against pathogens and herbivores, as well as potential medicinal activities, as seen in phylogenetically related groups to Brachystele.

Systemic histiocytic disorder in a jaguar (Panthera onca).

A 7-year-old captive female jaguar (Panthera onca) was presented with a 7-day history of dyspnoea and weight loss. Clinical examination revealed hepatomegaly and elevated serum alanine aminotransferase activity. Pulmonary ultrasonography revealed comet-tail images and an alveolar pattern was detected on thoracic radiography. Due to the poor prognosis, the jaguar was euthanized after 10 days. At necropsy, the main gross findings were hepatomegaly, splenomegaly and multifocal to coalescent, slightly elevated grey areas in the lungs. Histological examination revealed neoplastic proliferation of pleomorphic histiocytes arranged in cohesive sheets in the lungs, liver, spleen, kidneys and lymph nodes. Neoplastic cells had intense immunolabelling for vimentin and ionized calcium-binding adaptor molecule 1, and were immunonegative for pancytokeratin, E-cadherin, CD20, CD3 and CD79α. These findings were compatible with a systemic histiocytic disorder, distinct from any well-defined histiocytic proliferative disease in domestic animals.