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1.
Med Res Rev ; 44(5): 2078-2111, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-38530106

RESUMO

As the world population ages, there will be an increasing need for effective therapies for aging-associated neurodegenerative disorders, which remain untreatable. Dementia due to Alzheimer's disease (AD) is one of the leading neurological diseases in the aging population. Current therapeutic approaches to treat this disorder are solely symptomatic, making the need for new molecular entities acting on the causes of the disease extremely urgent. One of the potential solutions is to use compounds that are already in the market. The structures have known pharmacokinetics, pharmacodynamics, toxicity profiles, and patient data available in several countries. Several drugs have been used successfully to treat diseases different from their original purposes, such as autoimmunity and peripheral inflammation. Herein, we divulge the repurposing of drugs in the area of neurodegenerative diseases, focusing on the therapeutic potential of antineoplastics to treat dementia due to AD and dementia. We briefly touch upon the shared pathological mechanism between AD and cancer and drug repurposing strategies, with a focus on artificial intelligence. Next, we bring out the current status of research on the development of drugs, provide supporting evidence from retrospective, clinical, and preclinical studies on antineoplastic use, and bring in new areas, such as repurposing drugs for the prion-like spreading of pathologies in treating AD.


Assuntos
Doença de Alzheimer , Antineoplásicos , Demência , Reposicionamento de Medicamentos , Humanos , Doença de Alzheimer/tratamento farmacológico , Animais , Demência/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Estudos Observacionais como Assunto , Avaliação Pré-Clínica de Medicamentos
2.
Brief Bioinform ; 23(1)2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-34472587

RESUMO

Chemosensitivity assays are commonly used for preclinical drug discovery and clinical trial optimization. However, data from independent assays are often discordant, largely attributed to uncharacterized variation in the experimental materials and protocols. We report here the launching of Minimal Information for Chemosensitivity Assays (MICHA), accessed via https://micha-protocol.org. Distinguished from existing efforts that are often lacking support from data integration tools, MICHA can automatically extract publicly available information to facilitate the assay annotation including: 1) compounds, 2) samples, 3) reagents and 4) data processing methods. For example, MICHA provides an integrative web server and database to obtain compound annotation including chemical structures, targets and disease indications. In addition, the annotation of cell line samples, assay protocols and literature references can be greatly eased by retrieving manually curated catalogues. Once the annotation is complete, MICHA can export a report that conforms to the FAIR principle (Findable, Accessible, Interoperable and Reusable) of drug screening studies. To consolidate the utility of MICHA, we provide FAIRified protocols from five major cancer drug screening studies as well as six recently conducted COVID-19 studies. With the MICHA web server and database, we envisage a wider adoption of a community-driven effort to improve the open access of drug sensitivity assays.

3.
J Nat Prod ; 87(4): 1306-1319, 2024 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-38482846

RESUMO

Advancements in small-molecule research have created the need for sensitive techniques to accurately study biological processes in living systems. Fluorescent-labeled probes have become indispensable tools, particularly those that use boron-dipyrromethene (BODIPY) dyes. Terpenes and terpenoids are organic compounds found in nature that offer diverse biological activities, and BODIPY-based probes play a crucial role in studying these compounds. Monoterpene-BODIPY conjugates have exhibited potential for staining bacterial and fungal cells. Sesquiterpene-BODIPY derivatives have been used to study sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), indicating their potential for drug development. Owing to their unique properties, diterpenes have been investigated using BODIPY conjugates to evaluate their mechanisms of action. Triterpene-BODIPY conjugates have been synthesized for biological studies, with different spacers affecting their cytotoxicity. Fluorescent probes, inspired by terpenoid-containing vitamins, have also been developed. Derivatives of tocopherol, coenzyme Q10, and vitamin K1 can provide insights into their oxidation-reduction abilities. All these probes have diverse applications, including the study of cell membranes to investigate immune responses and antioxidant properties. Further research in this field can help better understand and use terpenes and terpenoids in various biological contexts.


Assuntos
Compostos de Boro , Terpenos , Terpenos/química , Terpenos/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Estrutura Molecular , Corantes Fluorescentes/química , Humanos
4.
Eur J Public Health ; 34(2): 361-367, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38224266

RESUMO

BACKGROUND: A population-based cervical cancer screening programme is implemented in the Czech Republic. However, participation is insufficient among women over 50 years. This study aimed to estimate the potential improvement in participation through directly mailed HPV self-sampling kits (HPVssk) compared with standard invitation letters in women aged 50-65 non-participating in screening. METHODS: The study recruited 1564 eligible women (no cervical cancer screening in the last 3 years or more, no previous treatment associated with cervical lesions or cervical cancer). Eight hundred women were mailed with an HPVssk (HPVssk group), and 764 women were sent a standard invitation letter (control group) inviting them to a routine screening (Pap test). The primary outcome was a comparison of the overall participation rate between study groups using a binominal regression model. RESULTS: The participation rate in the HPVssk group was 13.4% [95% confidence interval (CI) 11.2-15.9%; 7.4% of women returned the HPVssk and 6.0% attended gynaecological examination] and 5.0% (95% CI 3.6-6.8%) in the control group. Using the binominal regression model, the difference between the groups was estimated as 7.6% (95% CI 5.0-10.2%; P < 0.001). In the HPVssk group, 22% of women who returned HPVssk had a positive result and 70% of them underwent a follow-up examination. CONCLUSIONS: Compared with traditional invitation letters, the direct mailing of the HPVssk achieved a significantly higher participation rate, along with a notable HPV positivity rate among HPVssk responders. This approach offers a potentially viable method for engaging women who have not yet attended a cervical screening programme.


Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Infecções por Papillomavirus/diagnóstico , Detecção Precoce de Câncer/métodos , Esfregaço Vaginal , República Tcheca/epidemiologia , Programas de Rastreamento/métodos
5.
J Enzyme Inhib Med Chem ; 39(1): 2367139, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38904149

RESUMO

Estradiol dimers (EDs) possess significant anticancer activity by targeting tubulin dynamics. In this study, we synthesised 12 EDs variants via copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, focusing on structural modifications within the aromatic bridge connecting two estradiol moieties. In vitro testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC50 = 0.38 µM in CCRF-CEM) and ED5 (IC50 = 0.71 µM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC50 = 1.61 µM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and in vitro assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an in silico model illustrating the probable binding modes of ED3 and ED5, suggesting that dimers with a simple linker and a single substituent on the aromatic central ring possess enhanced characteristics compared to more complex dimers.


Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Estradiol , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estradiol/farmacologia , Estradiol/química , Estradiol/síntese química , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Dimerização , Química Click , Linhagem Celular Tumoral
6.
J Neurochem ; 165(2): 149-161, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36892419

RESUMO

The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient.


Assuntos
Doença de Alzheimer , Vesículas Extracelulares , MicroRNAs , Humanos , MicroRNAs/genética , Doença de Alzheimer/genética , Envelhecimento/genética
7.
Mol Cancer ; 22(1): 15, 2023 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681803

RESUMO

BACKGROUND: Despite advances in early detection and therapies, cancer is still one of the most common causes of death worldwide. Since each tumor is unique, there is a need to implement personalized care and develop robust tools for monitoring treatment response to assess drug efficacy and prevent disease relapse. MAIN BODY: Recent developments in liquid biopsies have enabled real-time noninvasive monitoring of tumor burden through the detection of molecules shed by tumors in the blood. These molecules include circulating tumor nucleic acids (ctNAs), comprising cell-free DNA or RNA molecules passively and/or actively released from tumor cells. Often highlighted for their diagnostic, predictive, and prognostic potential, these biomarkers possess valuable information about tumor characteristics and evolution. While circulating tumor DNA (ctDNA) has been in the spotlight for the last decade, less is known about circulating tumor RNA (ctRNA). There are unanswered questions about why some tumors shed high amounts of ctNAs while others have undetectable levels. Also, there are gaps in our understanding of associations between tumor evolution and ctNA characteristics and shedding kinetics. In this review, we summarize current knowledge about ctNA biology and release mechanisms and put this information into the context of tumor evolution and clinical utility. CONCLUSIONS: A deeper understanding of the biology of ctDNA and ctRNA may inform the use of liquid biopsies in personalized medicine to improve cancer patient outcomes.


Assuntos
Ácidos Nucleicos Livres , Neoplasias , Células Neoplásicas Circulantes , Humanos , Ácidos Nucleicos Livres/genética , Relevância Clínica , Neoplasias/patologia , Biomarcadores Tumorais/genética , Biologia , RNA
8.
Biochem Biophys Res Commun ; 653: 102-105, 2023 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-36863211

RESUMO

Tauopathies are a group of neurodegenerative diseases categorised into three types, 3R, 4R, or 3R+4R (mixed) tauopathies, based on the tau isoforms that make up the aberrant filaments. It is supposed that all six tau isoforms share functional characteristics. However, differences in the neuropathological features associated with different tauopathies offer the possibility that disease progression and tau accumulation may vary depending on the isoform composition. The presence or absence of repeat 2 (R2) in the microtubule-binding domain defines the type of isoform, which might influence tau pathology associated with a particular tau isoform. Therefore, our study aimed to identify the differences in the seeding propensities of R2 and repeat 3 (R3) aggregates using HEK293T biosensor cells. We show that the seeding induced by R2 was generally higher than by R3 aggregates, and lower concentrations of R2 aggregates are sufficient to induce seeding. Next, we found that both R2 and R3 aggregates dose-dependently increased triton-insoluble Ser262 phosphorylation of native tau, which is only visible in cells seeded with higher concentrations (12.5 nM or 100 nM) of R2 and R3 aggregates, despite the seeding by the lower concentrations of R2 aggregates after 72 h. However, the accumulation of triton-insoluble pSer262 tau was visible earlier in cells induced with R2 than in R3 aggregates. Our findings suggest that the R2 region may contribute to the early and enhanced induction of tau aggregation and define the difference in disease progression and neuropathology of 4R tauopathies.


Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Proteínas tau/metabolismo , Células HEK293 , Tauopatias/patologia , Isoformas de Proteínas/metabolismo , Ligação Proteica , Doença de Alzheimer/patologia
9.
Bioorg Chem ; 131: 106334, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36592487

RESUMO

Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC50 = 1.53 µM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay.


Assuntos
Antineoplásicos , Etinilestradiol , Triazóis , Moduladores de Tubulina , Tubulina (Proteína) , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Etinilestradiol/química , Etinilestradiol/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Microtúbulos , Triazóis/química , Triazóis/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
10.
Nature ; 552(7684): 194-199, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29211715

RESUMO

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.


Assuntos
Dissuasores de Álcool , Alcoolismo/tratamento farmacológico , Antineoplásicos , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Adulto , Dissuasores de Álcool/farmacologia , Dissuasores de Álcool/uso terapêutico , Alcoolismo/epidemiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cobre/química , Dinamarca/epidemiologia , Dissulfiram/química , Feminino , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Proteínas Nucleares/química , Agregados Proteicos , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos
11.
BMC Anesthesiol ; 23(1): 64, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36855089

RESUMO

BACKGROUND: Opioids and epidural analgesia are a mainstay of perioperative analgesia but their influence on cancer recurrence remains unclear. Based on retrospective data, we found that cancer recurrence following colorectal cancer surgery correlates with the number of circulating tumor cells (CTCs) in the early postoperative period. Also, morphine- but not piritramide-based postoperative analgesia increases the presence of CTCs and shortens cancer-specific survival. The influence of epidural analgesia on CTCs has not been studied yet. METHODS: We intend to enroll 120 patients in four centers in this prospective randomized controlled trial. The study protocol has been approved by Ethics Committees in all participating centers. Patients undergoing radical open colorectal cancer surgery are randomized into epidural, morphine, and piritramide groups for perioperative analgesia. The primary outcome is the difference in the number of CTCs in the peripheral blood before surgery, on the second postoperative day, and 2-4 weeks after surgery. The number of CTCs is measured using molecular biology methods. Perioperative care is standardized, and relevant data is recorded. A secondary outcome, if feasible, would be the expression and activity of various receptor subtypes in cancer tissue. We intend to perform a 5-year follow-up with regard to metastasis development. DISCUSSION: The mode of perioperative analgesia favorably affecting cancer recurrence would decrease morbidity/mortality. To identify such techniques, trials with long-term follow-up periods seem suboptimal. Given complex oncological therapeutic strategies, such trials likely disable the separation of perioperative analgesia effects from other factors. We believe that early postoperative CTCs presence/dynamics may serve as a sensitive marker of various perioperative interventions´ influences on cancer recurrence. Importantly, it is unbiased to the influence of long-term factors and minimally invasive. Analysis of opioid/cannabinoid receptor subtypes in cancer tissue would improve understanding of underlying mechanisms and promote personalization of treatment. We are not aware of any similar ongoing studies. TRIAL REGISTRATION NUMBER: NCT03700411, registration date: October 3, 2018. STUDY STATUS: recruiting.


Assuntos
Analgesia Epidural , Neoplasias Colorretais , Células Neoplásicas Circulantes , Humanos , Analgésicos Opioides/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Recidiva Local de Neoplasia , Morfina , Neoplasias Colorretais/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
12.
Alzheimers Dement ; 19(8): 3537-3554, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36825691

RESUMO

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Plexo Corióideo/metabolismo , Plexo Corióideo/patologia , Proteômica , Envelhecimento , Inflamação
13.
Int J Mol Sci ; 24(24)2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38139353

RESUMO

The transcription factor c-Myc, a key regulator of cellular processes, has long been associated with roles in cell proliferation and apoptosis. This review analyses the multiple functions of c-Myc by examining the different c-Myc isoforms in detail. The impact of different c-Myc isoforms, in particular p64 and p67, on fundamental biological processes remains controversial. It is necessary to investigate the different isoforms in the context of proto-oncogenesis. The current knowledge base suggests that neoplastic lesions may possess the means for self-destruction via increased c-Myc activity. This review presents the most relevant information on the c-Myc locus and focuses on a number of isoforms, including p64 and p67. This compilation provides a basis for the development of therapeutic approaches that target the potent growth arresting and pro-apoptotic functions of c-Myc. This information can then be used to develop targeted interventions against specific isoforms with the aim of shifting the oncogenic effects of c-Myc from pro-proliferative to pro-apoptotic. The research summarised in this review can deepen our understanding of how c-Myc activity contributes to different cellular responses, which will be crucial in developing effective therapeutic strategies; for example, isoform-specific approaches may allow for precise modulation of c-Myc function.


Assuntos
Proteínas Proto-Oncogênicas c-myc , Apoptose , Proliferação de Células , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro
14.
Int J Mol Sci ; 24(4)2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36835311

RESUMO

Circulating tumor cells (CTCs) are released from primary tumors and transported through the body via blood or lymphatic vessels before settling to form micrometastases under suitable conditions. Accordingly, several studies have identified CTCs as a negative prognostic factor for survival in many types of cancer. CTCs also reflect the current heterogeneity and genetic and biological state of tumors; so, their study can provide valuable insights into tumor progression, cell senescence, and cancer dormancy. Diverse methods with differing specificity, utility, costs, and sensitivity have been developed for isolating and characterizing CTCs. Additionally, novel techniques with the potential to overcome the limitations of existing ones are being developed. This primary literature review describes the current and emerging methods for enriching, detecting, isolating, and characterizing CTCs.


Assuntos
Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patologia , Separação Celular/métodos
15.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674559

RESUMO

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its potential as a non-invasively acquired source of biomarkers and in understanding of molecular (patho)physiology of the female genital tract. The first objective of this work was to optimize experimental workflow for CM processing and the second was to assess differences in the proteomic composition of CM during natural ovulatory cycles obtained from intrauterine insemination (IUI) cycles and in vitro fertilization (IVF) cycles with controlled ovarian hyperstimulation. Proteomic analysis of CM samples revealed 4370 proteins involved in processes including neutrophil degranulation, cellular stress responses, and hemostasis. Differential expression analysis revealed 199 proteins enriched in IUI samples and 422 enriched in IVF. The proteins enriched in IUI were involved in phosphatidic acid synthesis, responses to external stimulus, and neutrophil degranulation, while those enriched in IVF samples were linked to neutrophil degranulation, formation of a cornified envelope and hemostasis. Subsequent analyses clarified the protein composition of the CM and how it is altered by hormonal stimulation of the uterus.


Assuntos
Muco do Colo Uterino , Inseminação Artificial , Humanos , Feminino , Proteoma , Proteômica , Fertilização in vitro , Biomarcadores
16.
Ceska Gynekol ; 88(1): 4-12, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36858967

RESUMO

Cervical mucus is a viscous fluid functioning as a cervix plug. Products of the endometrial and cervical glands can be detected in the cervical mucus. Cervical mucus is further enriched with transudate originating from the fallopian tubes and proteins originating from the ovaries, peritoneum and distant tissues. With increasing levels of ovarian estrogens, the properties of cervical mucus for possible collection and processing change appropriately. For these reasons, we chose a group of 10 patients treated in the center of assisted reproduction by controlled ovarian stimulation for in vitro fertilization. This study focuses on the proteomic characterization of cervical mucus and localizes the possible sources of the identified proteins. The most abundant proteins were extracellular proteins, mainly mucins; however, most of the identified proteins, present usually in lower quantities, were of intracellular origin. The tissue analysis revealed that proteins from female reproductive organs are also expressed in other tissues in addition to female reproductive organs, but also proteins specific to the testis, liver, placenta, retina, and cerebellum. This study confirms the suitability and high potential of cervical mucus as a source of proteomic bio-markers not only for the dia-gnosis of the female reproductive tract.


Assuntos
Muco do Colo Uterino , Proteoma , Gravidez , Masculino , Humanos , Feminino , Proteômica , Ovário , Exsudatos e Transudatos
17.
J Am Chem Soc ; 144(42): 19437-19446, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36245092

RESUMO

A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of diverse (hetero)aromatics with dibenzothiophene-S-oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2'-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2'-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.


Assuntos
Nucleosídeos , Ribonucleosídeos , Linhagem Celular Tumoral , Pirimidinas , Óxidos , Zinco , Oligonucleotídeos , Desoxirribonucleosídeos , Nucleosídeos de Purina
18.
Curr Issues Mol Biol ; 45(1): 33-50, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36661489

RESUMO

SARS-CoV-2 causes the complex and heterogeneous illness known as COVID-19. The disease primarily affects the respiratory system but can quickly become systemic, harming multiple organs and leading to long-lasting sequelae in some patients. Most infected individuals are asymptomatic or present mild symptoms. Antibodies, complement, and immune cells can efficiently eliminate the virus. However, 20% of individuals develop severe respiratory illness and multiple organ failure. Virus replication has been described in several organs in patients who died from COVID-19, suggesting a compromised immune response. Immunodeficiency and autoimmunity are responsible for this impairment and facilitate viral escape. Mutations in IFN signal transduction and T cell activation are responsible for the inadequate response in young individuals. Autoantibodies are accountable for secondary immunodeficiency in patients with severe infection or prolonged COVID-19. Antibodies against cytokines (interferons α, γ and ω, IL1ß, IL6, IL10, IL-17, IL21), chemokines, complement, nuclear proteins and DNA, anticardiolipin, and several extracellular proteins have been reported. The type and titer of autoantibodies depend on age and gender. Organ-specific autoantibodies have been described in prolonged COVID-19. Their role in the disease is under study. Autoimmunity and immunodeficiency should be screened as risk factors for severe or prolonged COVID-19.

19.
Blood Cells Mol Dis ; 97: 102690, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35871033

RESUMO

Diamond-Blackfan anemia (DBA) is predominantly underlined by mutations in genes encoding ribosomal proteins (RP); however, its etiology remains unexplained in approximately 25 % of patients. We previously reported a novel heterozygous RPS7 mutation hg38 chr2:g.3,580,153G > T p.V134F in one female patient and two asymptomatic family members, in whom mild anemia and increased erythrocyte adenosine deaminase (eADA) activity were detected. We observed that altered erythrocyte metabolism and oxidative stress which may negatively affect the lifespan of erythrocytes distinguishes the patient from her asymptomatic family members. Pathogenicity of the RPS7 p.V134F mutation was extensively validated including molecular defects in protein translational activity and ribosomal stress activation in the cellular model of this variant.


Assuntos
Anemia de Diamond-Blackfan , Proteínas Ribossômicas , Anemia de Diamond-Blackfan/genética , Eritrócitos/metabolismo , Feminino , Humanos , Mutação de Sentido Incorreto , Biossíntese de Proteínas , Proteínas Ribossômicas/genética
20.
Bioconjug Chem ; 33(10): 1825-1836, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36197842

RESUMO

As angiogenesis plays a key role in tumor growth and metastasis, the angiogenic process has attracted scientific interest as a target for diagnostic and therapeutic agents. Factors influencing angiogenesis include the vascular endothelial growth factor (VEGF) family and the two associated receptor types (VEGFR-1 and VEGFR-2). VEGFR-1/-2 detection and quantification in cancer lesions are essential for tumor process management. As a result of the advantageous pharmacokinetics and image contrast, peptides radiolabeled with PET emitters have become interesting tools for the visualization of VEGFR-1/-2-positive tumors. In this study, we prepared 68Ga-labeled peptides containing 15 (peptide 1) and 23 (peptide 2) amino acids as new PET tracers for tumor angiogenic process imaging. METHODS: The peptides were conjugated with NODAGA-tris(t-Bu ester) and subsequently radiolabeled with [68Ga]Ga-chloride. The prepared [68Ga]Ga-NODAGA-peptide 1 and [68Ga]Ga-NODAGA-peptide 2 were tested for radiochemical purity and saline/plasma stability. Consequently, the binding affinity toward VEGFRs was assessed in vitro on human glioblastoma and kidney carcinoma cells. The found peptide receptor affinity was compared with the calculated values in the PROtein binDIng enerGY prediction (PRODIGY) server. Finally, the biodistribution study was performed on BALB/c female mice to reveal the basic pharmacokinetic behavior of radiopeptides. RESULTS: The in vitro affinity testing of [68Ga]Ga-NODAGA-peptides 1 and 2 showed retained receptor binding as characterized by equilibrium dissociation constant (KD) values in the range of 0.5-1.2 µM and inhibitory concentration 50% (IC50) values in the range of 3.0-5.6 µM. Better binding properties of peptide 2 to VEGFR-1/-2 were found in the PRODIGY server. The biodistribution study on mice showed remarkable accumulation of both peptides in the kidneys and urinary bladder with a short half-life after intravenous application. The in vitro plasma stability of [68Ga]Ga-NODAGA-peptide 2 was superior to that of [68Ga]Ga-NODAGA-peptide 1. CONCLUSIONS: The obtained results demonstrated a high radiolabeling yield with no need for purification and preserved binding potency of 68Ga-labeled peptides 1 and 2 toward VEGFRs in cancer cells. The peptide-receptor protein interaction assessed in protein-peptide docking determined the strongest interaction of peptide 2 with domain 2 of VEGFR-2 in addition to a more acceptable plasma stability (t1/2 = 120 min) than that for peptide 1. We found both radiolabeled peptides very potent in their receptor binding, which makes them suitable imaging agents. The rapid transition of the radiopeptides into the urinary tract indicates suitable pharmacokinetic characteristics.


Assuntos
Radioisótopos de Gálio , Fator A de Crescimento do Endotélio Vascular , Animais , Feminino , Humanos , Camundongos , Radioisótopos de Gálio/química , Distribuição Tecidual , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Tomografia por Emissão de Pósitrons/métodos , Cloretos , Compostos Heterocíclicos com 1 Anel/química , Peptídeos/química , Receptores de Fatores de Crescimento do Endotélio Vascular , Camundongos Endogâmicos BALB C , Aminoácidos , Ésteres , Linhagem Celular Tumoral
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