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The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics.
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Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced patients. Besides, PC tumors are enriched with subpopulations of cancer stem cells (CSCs) that are resistant to the existing chemotherapeutic agents, which raises an important need for the identification of new drugs. To fill this gap, we have tested the anti-tumoral activity of microbial extracts, which chemical diversity offers a broad spectrum of potential new bioactive compounds. Extracts derived from the fungus Onychocola sp. CF-107644 were assayed via high throughput screening followed by bioassay-guided fractionation and resulted in the identification and isolation of six benzophenone derivatives with antitumoral activity: onychocolones A-F (#1-6). The structures of the compounds were established by spectroscopic methods, including ESI-TOF MS, 1D and 2D NMR analyses and X-ray diffraction. Compounds #1-4 significantly inhibited the growth of the pancreas tumoral cell lines, with low-micromolar Median Effective Doses (ED50s). Compound #1 (onychocolone A) was prioritized for further profiling due to its pro-apoptotic effect, which was further validated on 3D spheroids and pancreatic CSCs. Protein expression assays showed that the effect was mechanistically linked to the inhibition of MEK onco-signaling pathway. The efficacy of onychocolone A was also demonstrated in vivo by the reduction of tumor growth in a pancreatic xenograft mouse model generated by CSCs. Altogether, the data support that onychocolone A is a promising new small molecule for hit-to-lead development of a new treatment for PC.
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Antineoplásicos , Células Madre Neoplásicas , Neoplasias Pancreáticas , Transducción de Señal , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Animales , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Benzofenonas/farmacología , Benzofenonas/química , Ensayos Antitumor por Modelo de Xenoinjerto , Ascomicetos/química , Ratones Desnudos , Proliferación Celular/efectos de los fármacosRESUMEN
An early diagnosis of cancer is fundamental not only in regard to reducing its mortality rate but also in terms of counteracting the progression of the tumor in the initial stages. Breast cancer (BC) is the most common tumor pathology in women and the second deathliest cancer worldwide, although its survival rate is increasing thanks to improvements in screening programs. However, the most common techniques to detect a breast tumor tend to be time-consuming, unspecific or invasive. Herein, the use of untargeted hydrophilic interaction liquid chromatography-mass spectrometry analysis appears as an analytical technique with potential use for the early detection of biomarkers in liquid biopsies from BC patients. In this research, plasma samples from 134 BC patients were compared with 136 from healthy controls (HC), and multivariate statistical analyses showed a clear separation between four BC phenotypes (LA, LB, HER2, and TN) and the HC group. As a result, we identified two candidate biomarkers that discriminated between the groups under study with a VIP > 1 and an AUC of 0.958. Thus, targeting the specific aberrant metabolic pathways in future studies may allow for better molecular stratification or early detection of the disease.
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Biomarcadores de Tumor , Neoplasias de la Mama , Interacciones Hidrofóbicas e Hidrofílicas , Metabolómica , Humanos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Biomarcadores de Tumor/sangre , Biopsia Líquida/métodos , Metabolómica/métodos , Persona de Mediana Edad , Cromatografía Liquida/métodos , Anciano , Adulto , Espectrometría de Masas/métodos , Cromatografía Líquida con Espectrometría de MasasRESUMEN
OBJECTIVES: New drugs are required to treat neglected diseases caused by trypanosomatid parasites such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi. An Achilles' heel of these parasites is their heme auxotrophy; they have an absolute dependence on scavenging this molecule from the host, and trypanosomatid HRG heme transporters (TrypHRG) play an important role in this process. As these proteins are essential for the parasites and have low similarity with their human orthologue, they have been proposed as attractive therapeutic targets. Here, we have developed two yeast-based assays that allow an inexpensive high-throughput screening of TrypHRG inhibitors within a cellular context. METHODS: We first assessed that Leishmania major, Leishmania donovani and T. brucei HRG proteins were heterologously expressed in the digestive vacuole membrane of a mutant heme auxotrophic yeast strain. Here, TrypHRG imports hemoglobinderived heme into the cytosol, allowing mutant yeast to grow in the presence of low hemoglobin concentrations and promoting the activity of hemeproteins such as catalase, which was used as a reporter of cytosolic heme levels. RESULTS: In the presence of a TrypHRG inhibitor, both catalase activity (test 1) and yeast growth (test 2) were diminished, being easily monitored. The assays were then tested on a pilot scale for HTS purposes using a collection of repurposing drugs and food antioxidants. Some of the TrypHRG inhibitors identified in yeast presented strong trypanocidal and leishmanicidal activity in the submicromolar range, proving the potential of this approach. CONCLUSIONS: Cumulatively, it was shown that the inhibition bioassays developed were robust and applicable to large-scale HTS.
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Leishmania , Saccharomyces cerevisiae , Humanos , Saccharomyces cerevisiae/genética , Catalasa , Bioensayo , HemoRESUMEN
BACKGROUND: Malignant melanoma (MM) is a highly aggressive form of skin cancer whose incidence continues to rise worldwide. If diagnosed at an early stage, it has an excellent prognosis, but mortality increases significantly at advanced stages after distant spread. Unfortunately, early detection of aggressive melanoma remains a challenge. OBJECTIVES: To identify novel blood-circulating biomarkers that may be useful in the diagnosis of MM to guide patient counselling and appropriate disease management. METHODS: In this study, 105 serum samples from 26 healthy patients and 79 with MM were analysed using an untargeted approach by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to compare the metabolomic profiles of both conditions. Resulting data were subjected to both univariate and multivariate statistical analysis to select robust biomarkers. The classification model obtained from this analysis was further validated with an independent cohort of 12 patients with stage I MM. RESULTS: We successfully identified several lipidic metabolites differentially expressed in patients with stage I MM vs. healthy controls. Three of these metabolites were used to develop a classification model, which exhibited exceptional precision (0.92) and accuracy (0.94) when validated on an independent sample. CONCLUSIONS: These results demonstrate that metabolomics using LC-HRMS is a powerful tool to identify and quantify metabolites in bodily fluids that could serve as potential early diagnostic markers for MM.
Melanoma is a type of skin cancer that can be deadly if it is not detected at an early stage. Unfortunately, the early detection of melanoma is challenging. Our team has developed a model that could be used to predict whether a person has stage I malignant melanoma based on blood serum analysis. The model was trained on data from a group of people with melanoma and it was found to be accurate in predicting melanoma at an early stage. This means that the model could be used to identify people who have skin cancer before it progresses and becomes more complicated to treat. Although the researchers recommend that further studies are conducted to validate the model in a larger population of people, this research could help with the early diagnosis of melanoma and work toward improving survival rates.
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Melanoma , Neoplasias Cutáneas , Humanos , Proyectos Piloto , Detección Precoz del Cáncer , Metabolómica , Biomarcadores , Cromatografía Líquida con Espectrometría de MasasRESUMEN
The increase in global travel and the incorrect and excessive use of antibiotics has led to an unprecedented rise in antibiotic resistance in bacterial and fungal populations. To overcome these problems, novel bioactive natural products must be discovered, which may be found in underexplored environments, such as estuarine habitats. In the present work, estuarine actinomycetotal strains were isolated with conventional and iChip techniques from the Tagus estuary in Alcochete, Portugal, and analysed for different antimicrobial bioactivities. Extracts were produced from the isolated cultures and tested for bioactivity against Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Aspergillus fumigatus ATCC 240305, Candida albicans ATCC 10231 and Trichophyton rubrum FF5. Furthermore, bioactive extracts were subjected to dereplication by high-performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) to putatively identify their chemical components. In total, 105 isolates belonging to 3 genera were obtained. One which was isolated, MTZ3.1 T, represents a described novel taxon for which the name Streptomyces meridianus was proposed. Regarding the bioactivity testing, extracts from 12 strains proved to be active against S. aureus, 2 against E. coli, 4 against A. fumigatus, 3 against C. albicans and 10 against T. rubrum. Dereplication of bioactive extracts showed the presence of 28 known bioactive molecules, 35 hits have one or more possible matches in the DNP and 18 undescribed ones. These results showed that the isolated bacteria might be the source of new bioactive natural products.
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An appealing strategy for finding novel bioactive molecules in Nature consists in exploring underrepresented and -studied microorganisms. Here, we investigated the antimicrobial and tumoral anti-proliferative bioactivities of twenty-three marine and estuarine bacteria of the fascinating phylum Planctomycetota. This was achieved through extraction of compounds produced by the Planctomycetota cultured in oligotrophic medium followed by an antimicrobial screening against ten relevant human pathogens including Gram-positive and Gram-negative bacteria, and fungi. Cytotoxic effects of the extracts were also evaluated against five tumoral cell lines. Moderate to potent activities were obtained against Enterococcus faecalis, methicillin-sensitive and methicillin-resistant Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant Enterococcus faecium. Anti-fungal effects were observed against Trichophyton rubrum, Candida albicans and Aspergillus fumigatus. The highest cytotoxic effects were observed against human breast, pancreas and melanoma tumoral cell lines. Novipirellula caenicola and Rhodopirellula spp. strains displayed the widest spectrum of bioactivities while Rubinisphaera margarita ICM_H10T affected all Gram-positive bacteria tested. LC-HRMS analysis of the extracts did not reveal the presence of any known bioactive natural product, suggesting that the observed activities are most likely caused by novel molecules, that need identification. In summary, we expanded the scope of planctomycetal species investigated for bioactivities and demonstrated that various strains are promising sources of novel bioactive compounds, which reenforces the potential biotechnological prospects offered by Planctomycetota.
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Staphylococcus aureus Resistente a Meticilina , Planctomicetos , Humanos , Bacterias Gramnegativas , Antibacterianos/farmacología , Vancomicina , Bacterias GrampositivasRESUMEN
IMPORTANCE: The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production. The implementation of a high-throughput screening platform using the betacoronavirus OC43 in a human cell line infection model has provided proof of concept of the approach and has allowed for the rapid and efficient evaluation of 1,280 microbial extracts. The identification of several active compounds validates the potential of the platform for the search for new compounds with antiviral capacity.
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Productos Biológicos , Coronavirus Humano OC43 , Humanos , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Pandemias , Línea Celular , Antivirales/farmacologíaRESUMEN
Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field. Industrial-scale HTS of NP libraries can be limited due to the difficulties entailed in working with tiny extract volumes and the variability in viscosity of NP extracts. For these reasons, the implementation of new technologies to miniaturize different reagent volumes grows to be fundamental. Since Acoustic Droplet Ejection (ADE) emerged as a helpful tool in HTS campaigns for the transference of compound libraries. The aim of this work was to test the effectiveness of ADE for the dispensation of NP extract libraries in cell-based HTS assays.
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Neglected diseases caused by kinetoplastid parasites are a health burden in tropical and subtropical countries. The need to create safe and effective medicines to improve treatment remains a priority. Microbial natural products are a source of chemical diversity that provides a valuable approach for identifying new drug candidates. We recently reported the discovery and bioassay-guided isolation of a novel family of macrolides with antiplasmodial activity. The novel family of four potent antimalarial macrolides, strasseriolides A-D, was isolated from cultures of Strasseria geniculata CF-247251, a fungal strain obtained from plant tissues. In the present study, we analyze these strasseriolides for activity against kinetoplastid protozoan parasites, namely, Trypanosoma brucei brucei, Leishmania donovani and Trypanosoma cruzi. Compounds exhibited mostly low activities against T. b. brucei, yet notable growth inhibition and selectivity were observed for strasseriolides C and D in the clinically relevant intracellular T. cruzi and L. donovani amastigotes with EC50 values in the low micromolar range. Compound C is fast-acting and active against both intracellular and trypomastigote forms of T. cruzi. While cell cycle defects were not identified, prominent morphological changes were visualized by differential interference contrast microscopy and smaller and rounded parasites were visualized upon exposure to strasseriolide C. Moreover, compound C lowers parasitaemia in vivo in acute models of infection of Chagas disease. Hence, strasseriolide C is a novel natural product active against different forms of T. cruzi in vitro and in vivo. The study provides an avenue for blocking infection of new cells, a strategy that could additionally contribute to avoid treatment failure.
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Enfermedad de Chagas , Parásitos , Trypanosoma brucei brucei , Trypanosoma cruzi , Animales , Enfermedad de Chagas/tratamiento farmacológico , Macrólidos/farmacologíaRESUMEN
Antimicrobial resistance can be considered a hidden global pandemic and research must be reinforced for the discovery of new antibiotics. The spirotetronate class of polyketides, with more than 100 bioactive compounds described to date, has recently grown with the discovery of phocoenamicins, compounds displaying different antibiotic activities. Three marine Micromonospora strains (CA-214671, CA-214658 and CA-218877), identified as phocoenamicins producers, were chosen to scale up their production and LC/HRMS analyses proved that EtOAc extracts from their culture broths produce several structurally related compounds not disclosed before. Herein, we report the production, isolation and structural elucidation of two new phocoenamicins, phocoenamicins D and E (1-2), along with the known phocoenamicin, phocoenamicins B and C (3-5), as well as maklamicin (7) and maklamicin B (6), the latter being reported for the first time as a natural product. All the isolated compounds were tested against various human pathogens and revealed diverse strong to negligible activity against methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis H37Ra, Enterococcus faecium and Enterococcus faecalis. Their cell viability was also evaluated against the human liver adenocarcinoma cell line (Hep G2), demonstrating weak or no cytotoxicity. Lastly, the safety of the major compounds obtained, phocoenamicin (3), phocoenamicin B (4) and maklamicin (7), was tested against zebrafish eleuthero embryos and all of them displayed no toxicity up to a concentration of 25 µM.
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Staphylococcus aureus Resistente a Meticilina , Micromonospora , Humanos , Animales , Pez Cebra , Macrólidos/farmacología , Antibacterianos/farmacologíaRESUMEN
Cancer is considered one of the main causes of human death worldwide, being characterized by an alteration of the oxidative metabolism. Many natural compounds from plant origin with anti-tumor attributes have been described. Among them, capsaicin, which is the molecule responsible for the pungency in hot pepper fruits, has been reported to show antioxidant, anti-inflammatory, and analgesic activities, as well as anti-proliferative properties against cancer. Thus, in this work, the potential anti-proliferative activity of pepper (Capsicum annuum L.) fruits from diverse varieties with different capsaicin contents (California < Piquillo < Padrón < Alegría riojana) against several tumor cell lines (lung, melanoma, hepatoma, colon, breast, pancreas, and prostate) has been investigated. The results showed that the capsaicin content in pepper fruits did not correspond with their anti-proliferative activity against tumor cell lines. By contrast, the greatest activity was promoted by the pepper tissues which contained the lowest capsaicin amount. This indicates that other compounds different from capsaicin have this anti-tumor potentiality in pepper fruits. Based on this, green fruits from the Alegría riojana variety, which has negligible capsaicin levels, was used to study the effect on the oxidative and redox metabolism of tumor cell lines from liver (Hep-G2) and pancreas (MIA PaCa-2). Different parameters from both lines treated with crude pepper fruit extracts were determined including protein nitration and protein S-nitrosation (two post-translational modifications (PTMs) promoted by nitric oxide), the antioxidant capacity, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), among others. In addition, the activity of the NADPH-generating enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), and NADP-isocitrate dehydrogenase (NADP-ICDH) was followed. Our data revealed that the treatment of both cell lines with pepper fruit extracts altered their antioxidant capacity, enhanced their catalase activity, and considerably reduced the activity of the NADPH-generating enzymes. As a consequence, less H2O2 and NADPH seem to be available to cells, thus avoiding cell proliferation and possibly triggering cell death in both cell lines.
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A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 µg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 µg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.
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Staphylococcus aureus , Staphylococcus aureus Resistente a Vancomicina , Animales , Ratones , Staphylococcus aureus/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV , Pruebas de Sensibilidad MicrobianaRESUMEN
Memnoniella is a fungal genus from which a wide range of diverse biologically active compounds have been isolated. A Memnoniella dichroa CF-080171 extract was identified to exhibit potent activity against Plasmodium falciparum 3D7 and Trypanosoma cruzi Tulahuen whole parasites in a high-throughput screening (HTS) campaign of microbial extracts from the Fundación MEDINA's collection. Bioassay-guided isolation of the active metabolites from this extract afforded eight new meroterpenoids of varying potencies, namely, memnobotrins C-E (1-3), a glycosylated isobenzofuranone (4), a tricyclic isobenzofuranone (5), a tetracyclic benzopyrane (6), a tetracyclic isobenzofuranone (7), and a pentacyclic isobenzofuranone (8). The structures of the isolated compounds were established by (+)-ESI-TOF high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Compounds 1, 2, and 4 exhibited potent antiparasitic activity against P. falciparum 3D7 (EC50 0.04-0.243 µM) and T. cruzi Tulahuen (EC50 0.266-1.37 µM) parasites, as well as cytotoxic activity against HepG2 tumoral liver cells (EC50 1.20-4.84 µM). The remaining compounds (3, 5-8) showed moderate or no activity against the above-mentioned parasites and cells.
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We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
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Acinetobacter baumannii , Inhibidores de Topoisomerasa II , Humanos , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Pseudomonas aeruginosa/metabolismo , Acinetobacter baumannii/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Escherichia coli/metabolismo , Benzotiazoles , Pruebas de Sensibilidad Microbiana , Girasa de ADN/metabolismoRESUMEN
As parasitoses intestinais ainda constituem um problema de saúde pública no Brasil, especialmente nas regiões onde o saneamento básico e condições socioeconômicas são frágeis, como na região Nordeste. São um conjunto de doenças causadas por parasitas helmínticos ou protozoários, que acometem o intestino humano, causando sintomas, como diarreia, dor abdominal, astenia, náuseas, vômitos, entre outros. Seu diagnóstico é feito pelo parasitológico de fezes e o tratamento é baseado no uso de anti-protozoários ou anti-helmínticos. Objetivo: analisar os principais aspectos das parasitoses intestinais presentes no Nordeste, identificando aquelas mais prevalentes e as populações de maiores riscos. Metodologia: o estudo foi do tipo descritivo, utilizando-se uma revisão integrativa de literatura do período de 2012 a 2021, nas bases de dados eletrônicas Scielo, BVS e Google Acadêmico. Para o processo de busca e análise dos artigos, foi utilizado o diagrama flow. Todos os dados da pesquisa foram analisados no Microsoft Word e, posteriormente os resultados foram transformados em quadros e tabelas para melhor organização e interpretação das informações colhidas. Resultados: observou-se, a partir da análise dos 10 artigos, uma variação de 26,00% a 92,85% na taxa de infecções por parasitas intestinais na região Nordeste, em diversas populações, desde pré-escolares, escolares e adultos. Os fatores de risco que estiveram associados ao desenvolvimento, foram: falta de higiene pessoal e dos alimentos, ausência ou precariedade dos serviços de saneamento básico, baixa escolaridade e renda dos pais, qualidade da água de beber e práticas de andar descalço por parte das crianças. Considerações finais: Os resultados apontam para a necessidade de medidas preventivas e tratamento das enteroparasitoses, como mudanças de hábitos de higiene e melhorias nas condições de vida, como o acesso à água tratada e saneamento básico adequado. Além disso, é importante que surjam mais estudos epidemiológicos para subsidiar medidas de controle e prevenção adequadas e eficazes.
Intestinal parasites are still a public health problem in Brazil, especially in regions where basic sanitation and socioeconomic conditions are fragile, as in the Northeast region. They are a set of diseases caused by helminthic or protozoan parasites, which affect the human intestine, causing symptoms such as diarrhea, abdominal pain, asthenia, nausea, vomiting, among others. Its diagnosis is made by fecal parasitology and treatment is based on the use of anti-protozoal or anthelmintic agents. Objective: to analyze the main aspects of intestinal parasites present in the Northeast, identifying the most prevalent ones and the populations at greatest risk. Methodology: the study was descriptive, using an integrative literature review from 2012 to 2021, in the electronic databases Scielo, BVS and Google Scholar. For the process of searching and analyzing the articles, the flow diagram was used. All survey data were analyzed in Microsoft Excel and, later, the results were transformed into graphs and tables for better interpretation of the collected information. RESULTS: from the analysis of the 10 articles, a variation from 26.00% to 92.85% was observed in the rate of infections by intestinal parasites in the Northeast region, in different populations, from preschoolers, schoolchildren and adults. The risk factors that were associated with development were: lack of personal hygiene and food, absence or precariousness of basic sanitation services, low parental education and income, quality of drinking water and practices of walking barefoot by children. Final Considerations: The results point to the need for preventive measures and treatment of intestinal parasites, such as changes in hygiene habits and improvements in living conditions, such as access to treated water and adequate basic sanitation. In addition, it is important that more epidemiological studies appear to support appropriate and effective control and prevention measures.
Las parasitosis intestinales siguen siendo un problema de salud pública en Brasil, especialmente en regiones donde el saneamiento básico y las condiciones socioeconómicas son frágiles, como en la región Nordeste. Son un conjunto de enfermedades causadas por parásitos helmínticos o protozoarios, que afectan el intestino humano, causando síntomas como diarrea, dolor abdominal, astenia, náuseas, vómitos, entre otros. Su diagnóstico se realiza mediante parasitología fecal y el tratamiento se basa en el uso de agentes antiprotozoarios o antihelmínticos. Objetivo: analizar los principales aspectos de los parásitos intestinales presentes en el Nordeste, identificando los más prevalentes y las poblaciones de mayor riesgo. Metodología: el estudio fue descriptivo, utilizando una revisión bibliográfica integradora de 2012 a 2021, en las bases de datos electrónicas Scielo, BVS y Google Scholar. Para el proceso de búsqueda y análisis de los artículos, se utilizó el diagrama de flujo. Todos los datos de la encuesta fueron analizados en Microsoft Excel y, posteriormente, los resultados fueron transformados en gráficos y tablas para una mejor interpretación de la información recogida. Resultados: a partir del análisis de los 10 artículos, se observó una variación de 26,00% a 92,85% en la tasa de infecciones por parásitos intestinales en la región Nordeste, en diferentes poblaciones, desde preescolares, escolares y adultos. Los factores de riesgo que se asociaron al desarrollo fueron: falta de higiene personal y alimentaria, ausencia o precariedad de servicios de saneamiento básico, baja escolaridad e ingresos de los padres, calidad del agua de consumo y prácticas de caminar descalzo por parte de los niños. Consideraciones Finales: Los resultados apuntan a la necesidad de medidas preventivas y de tratamiento de los parásitos intestinales, como cambios en los hábitos de higiene y mejoras en las condiciones de vida, como el acceso a agua tratada y a un saneamiento básico adecuado. Además, es importante que aparezcan más estudios epidemiológicos que respalden medidas de control y prevención adecuadas y eficaces.
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Over the past few years, new technological and scientific advances have reinforced the field of natural product discovery. The spirotetronate class of natural products has recently grown with the discovery of phocoenamicins, natural actinomycete derived compounds that possess different antibiotic activities. Exploring the MEDINA's strain collection, 27 actinomycete strains, including three marine-derived and 24 terrestrial strains, were identified as possible phocoenamicins producers and their taxonomic identification by 16S rDNA sequencing showed that they all belong to the Micromonospora genus. Using an OSMAC approach, all the strains were cultivated in 10 different media each, resulting in 270 fermentations, whose extracts were analyzed by LC-HRMS and subjected to High-throughput screening (HTS) against methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis H37Ra and Mycobacterium bovis. The combination of LC-UV-HRMS analyses, metabolomics analysis and molecular networking (GNPS) revealed that they produce several related spirotetronates not disclosed before. Variations in the culture media were identified as the most determining factor for phocoenamicin production and the best producer strains and media were established. Herein, we reported the chemically diverse production and metabolic profiling of Micromonospora sp. strains, including the known phocoenamicins and maklamicin, reported for the first time as being related to this family of compounds, as well as the bioactivity of their crude extracts. Although our findings do not confirm previous statements about phocoenamicins production only in unique marine environments, they have identified marine-derived Micromonospora species as the best producers of phocoenamicins in terms of both the abundance in their extracts of some major members of the structural class and the variety of molecular structures produced.
Asunto(s)
Actinobacteria , Staphylococcus aureus Resistente a Meticilina , Micromonospora , Micromonospora/química , Antibacterianos/química , Estructura Molecular , Actinobacteria/genéticaRESUMEN
The present study characterizes the oral pharmacokinetics of D-Pinitol, a natural insulin mimetic inositol, in human healthy volunteers (14 males and 11 females). D-Pinitol absorption was studied in (a) subjects receiving a single oral dose of 15 mg/kg (n = 10), or (b) 5 mg/kg pure D-Pinitol (n = 6), and (c) subjects receiving D-Pinitol as part of carbohydrate-containing carob pods-derived syrup with a 3.2% D-Pinitol (Dose of 1600 mg/subject, n = 9). The volunteers received a randomly assigned single dose of either D-Pinitol or carob pod-derived syrup. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 1440 min after intake. Plasma concentration of D-Pinitol was measured and pharmacokinetic parameters obtained. The data indicate that when given alone, the oral absorption of D-Pinitol is dose-dependent and of extended duration, with a Tmax reached after almost 4 h, and a half-life greater than 5 h. When the source of D-Pinitol was a carob pods-derived syrup, Cmax was reduced to 40% of the expected based on the data of D-Pinitol alone, suggesting a reduced absorption probably because of competition with monosaccharide transport. In this group, Tmax was reached before that of D-Pinitol alone, but the estimated half-life remained the same. In the D-Pinitol groups, plasma concentrations of glucose, insulin, glucagon, ghrelin, free fatty acids, and pituitary hormones were additionally measured. A dose of 15 mg/kg of D-Pinitol did not affect glucose levels in healthy volunteers, but reduced insulin and increased glucagon and ghrelin concentrations. D-Pinitol did not increase other hormones known to enhance plasma glucose, such as cortisol or GH, which were surprisingly reduced after the ingestion of this inositol. Other pituitary hormones (gonadotropins, prolactin, and thyroid-stimulating hormone) were not affected after D-Pinitol ingestion. In a conclusion, D-Pinitol is absorbed through the oral route, having an extended half-life and displaying the pharmacological profile of an endocrine pancreas protector, a pharmacological activity of potential interest for the treatment or prevention of insulin resistance-associated conditions.
Asunto(s)
Fabaceae , Ayuno , Glucemia , Ácidos Grasos no Esterificados , Femenino , Ghrelina , Glucagón , Glucosa , Voluntarios Sanos , Humanos , Hidrocortisona , Inositol/análogos & derivados , Insulina , Masculino , Prolactina , TirotropinaRESUMEN
Oceans hold a stunning number of unique microorganisms, which remain unstudied by culture-dependent methods due to failures in establishing the right conditions for these organisms to grow. In this work, an isolation effort inspired by the iChip was performed using marine sediments from Memoria beach, Portugal. The isolates obtained were identified by 16S rRNA gene analysis, fingerprinted using BOX-PCR and ERIC-PCR, searched for the putative presence of secondary metabolism genes associated with polyketide synthase I (PKS-I) and non-ribosomal peptide synthetases (NRPS), screened for antimicrobial activity against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213, and had bioactive extracts dereplicated by LC/HRMS. Of the 158 isolated strains, 96 were affiliated with the phylum Actinomycetota, PKS-I and NRPS genes were detected in 53 actinomycetotal strains, and 11 proved to be bioactive (10 against E. coli, 1 against S. aureus and 1 against both pathogens). Further bioactivities were explored using an "one strain many compounds" approach, with six strains showing continued bioactivity and one showing a novel one. Extract dereplication showed the presence of several known bioactive molecules and potential novel ones in the bioactive extracts. These results indicate the use of the bacteria isolated here as sources of new bioactive natural products.
RESUMEN
The discovery of new bioactive compounds is an invaluable aid to the development of new drugs. Strategies for finding novel molecules can focus on the exploitation of less studied organisms and ecosystems such as planctomycetes and brackish habitats. The unique cell biology of the underexplored Planctomycetota mean it is of particular interest. In this study, we aimed to isolate planctomycetes from the estuary of the Tejo river (Portugal). To reach this goal, macroalgae, water and sediments were sampled and diverse media and isolation techniques applied. Sixty-nine planctomycetal strains were brought into pure culture. An analysis of the 16S rRNA genes found that the majority of the isolates were affiliated to the genus Rhodopirellula. Putative novel taxa belonging to genera Stieleria and Rhodopirellula were also isolated and characterized morphologically. Enterobacterial repetitive intergenic consensus fingerprinting analyses showed higher diversity and different genotypes within close strains. Relevant biosynthetic gene clusters were found in most isolates and acetone extracts from representative strains exhibited mild antimicrobial activities against Escherichia coli and Staphylococcus aureus. Our work has not only enlarged the number and diversity of cultured planctomycetes but has also shown the potential for the discovery of bioactive compounds from the novel taxa.