RESUMO
Palladium(II) complexes have stimulated research interest mainly due to their in vitro cytotoxicity against various cancer cell lines and their low cytotoxicity in healthy cells. Thus, in this work, we combined Pd(II)/phosphine systems with the natural product curcumin as a ligand, obtaining a series of complexes, [Pd(cur)(PPh3)2]PF6 (A1), [Pd(cur)(dppe)]PF6 (A2), [Pd(cur)(dppp)]PF6 (A3), [Pd(cur)(dppb)]PF6 (A4) and [Pd(cur)(dppf)]PF6 (A5), where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1'-bis(diphenylphosphino)ferrocene (P-P), which were characterized by elemental analysis, molar conductivity analysis, and mass, NMR (1H, 13C, 31P{1H}), UV-vis, and IR spectroscopies, and four of them (A1, A2, A4, and A5) by X-ray crystallography. The in vitro cell viability of the complexes A1-A5, cisplatin, and the free ligand curcumin against MDA-MB-231 (human triple-negative breast tumor cells), SK-BR-3 (human breast tumor cells), A549 (human lung tumor cells), MRC-5 (non-tumor human lung cells), A2780 (human ovarian carcinoma cells), and A2780cis (cisplatin-resistant human ovarian carcinoma cells), was evaluated by the MTT colorimetric assay. For the tumor cell lines tested, the complexes showed good anticancer activities. The results showed that in general the complexes had lower IC50 values than free curcumin and the precursors [PdCl2(P-P)]. IC50 results obtained for the A1-A5 complexes, in the MCF-7 cell line, are similar to those that had already been observed for some Pd/bipy/curcumin complexes. In the MDA-MB-231 cell line, complexes A1 and A5 stood out, with their lowest IC50 values, around 5 µmol L-1, and the complexes appeared to be more active (lower IC50 values) against the ovarian cell lines. Complex A1 was 23 and 22-fold more cytotoxic than cisplatin, against the A2780 and A2780cis cells, respectively. The complex A1 was studied on A2780cis cells and it was found that this complex inhibits colony formation and induces cell cycle arrest in the sub-G1 phase in a concentration-dependent manner and leads to cell death by apoptosis. The DCFDA assay revealed a potent ROS induction for complex A1.
RESUMO
The field of blood-based biomarkers for Alzheimer's disease (AD) has advanced at an incredible pace, especially after the development of sensitive analytic platforms that can facilitate large-scale screening. Such screening will be important when more sophisticated diagnostic methods are scarce and expensive. Thus, blood-based biomarkers can potentially reduce diagnosis inequities among populations from different socioeconomic contexts. This large-scale screening can be performed so that older adults at risk of cognitive decline assessed using these methods can then undergo more complete assessments with classic biomarkers, increasing diagnosis efficiency and reducing costs to the health systems. Blood-based biomarkers can also aid in assessing the effect of new disease-modifying treatments. This paper reviews recent advances in the area, focusing on the following leading candidates for blood-based biomarkers: amyloid-beta (Aß), phosphorylated tau isoforms (p-tau), neurofilament light (NfL), and glial fibrillary acidic (GFAP) proteins, as well as on new candidates, Neuron-Derived Exosomes contents (NDEs) and Transactive response DNA-binding protein-43 (TDP-43), based on data from longitudinal observational cohort studies. The underlying challenges of validating and incorporating these biomarkers into routine clinical practice and primary care settings are also discussed. Importantly, challenges related to the underrepresentation of ethnic minorities and socioeconomically disadvantaged persons must be considered. If these challenges are overcome, a new time of cost-effective blood-based biomarkers for AD could represent the future of clinical procedures in the field and, together with continued prevention strategies, the beginning of an era with a lower incidence of dementia worldwide.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Disfunção Cognitiva/diagnóstico , Estudos de Coortes , Biomarcadores , Proteínas tauRESUMO
We describe the synthesis, physicochemical characterization, and in vitro antitumor assays of four novel analogous ruthenium(II) complexes with general formula cis-[RuII(N-L)(P-P)2]PF6, where P-P = bis(diphenylphosphine)methane (dppm, in complexes 1 and 2) or bis(diphenylphosphine)ethane (dppe, in complexes 3 and 4) and N-L = 5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (Btsc, in complexes 1 and 3) or 5,6-diphenyltriazine-3-one (Bsc, in complexes 2 and 4). The data were consistent with cis arrangement of the biphosphine ligands. For the Btsc and Bsc ligands, the data pointed to monoanionic bidentate coordination to ruthenium(II) through N,S and N,O, respectively. Single-crystal X-ray diffraction showed that complex 1 crystallized in the monoclinic system, space group P21/c. Determination of the cytotoxicity profiles of complexes 1-4 gave SI values ranging from 1.19 to 3.50 against the human lung adenocarcinoma cell line A549 and the non-tumor lung cell line MRC-5. Although the molecular docking studies suggested that the interaction between DNA and complex 4 was energetically favorable, the experimental results showed that they interacted weakly. Overall, our results demonstrated that these novel ruthenium(II) complexes have interesting in vitro antitumor potential and this study may contribute to further studies in medicinal inorganic chemistry.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias Pulmonares , Rutênio , Semicarbazonas , Humanos , Complexos de Coordenação/química , Rutênio/farmacologia , Rutênio/química , Linhagem Celular Tumoral , Ligantes , Simulação de Acoplamento Molecular , Semicarbazonas/farmacologia , Antineoplásicos/química , Apoptose , Neoplasias Pulmonares/tratamento farmacológico , Movimento Celular , PulmãoRESUMO
We report here on three new ruthenium(II) complexes, [Ru(DPEPhos)(mtz)(bipy)]PF6 (Ru1), [Ru(DPEPhos)(mmi)(bipy)]PF6 (Ru2) and [Ru(DPEPhos)(dmp)(bipy)]PF6 (Ru3). DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2-mercaptopyrimidine and bipy = 2,2'-bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 - Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC50 values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC50 value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 - Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Humanos , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Estrutura Molecular , Éteres , Rutênio/químicaRESUMO
Biomarkers capable of identifying and distinguishing types of dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), Lewy body dementia (LBD), and frontotemporal dementia (FTD), have become increasingly relentless. Studies on possible biomarker proteins in the blood that can help formulate new diagnostic proposals and therapeutic visions of different types of dementia are needed. However, due to several limitations of these biomarkers, especially in discerning dementia, their clinical applications are still undetermined. Thus, updating biomarker blood proteins that can help in the diagnosis and discrimination of these main dementia conditions is essential to enable new pharmacological and clinical management strategies with specificities for each type of dementia. This paper aimed to review the literature concerning protein bloodbased AD and non-AD biomarkers as new pharmacological targets and/or therapeutic strategies. Recent findings related to protein-based AD, PDD, LBD, and FTD biomarkers are focused on in this review. Protein biomarkers are classified according to the pathophysiology of the dementia types. The diagnosis and distinction of dementia through protein biomarkers is still a challenge. The lack of exclusive biomarkers for each type of dementia highlights the need for further studies in this field. Only after this, blood biomarkers may have a valid use in clinical practice as they are promising to help in the diagnosis and in the differentiation of diseases.
Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença por Corpos de Lewy , Doença de Parkinson , Doença de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Humanos , Doença por Corpos de Lewy/diagnóstico , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológicoRESUMO
We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 µM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Rutênio/farmacologia , Tioureia/análogos & derivados , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/uso terapêutico , Feminino , Humanos , Compostos de Rutênio/síntese química , Compostos de Rutênio/uso terapêutico , Tioureia/químicaRESUMO
Six complexes with the general formula [Cu(acylthioureato)(PPh3)2] were synthesized and characterized using spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), mass spectrometry, elemental analysis, and X-ray diffraction. Interpretation of the in vitro cytotoxicity data of Cu(I) complexes took into account their stability in cell culture medium. DFT calculations showed that NMR properties, such as the shielding of carbon atoms, are affected by relativistic effects, supported by the ZORA Hamiltonian in the theoretical calculations. Additionally, the calculation of the energies of the frontier molecular orbitals predicted that the structural changes of the acylthiourea ligands did not cause marked changes in the reactivity descriptors. All complexes were cytotoxic to the evaluated tumor cell lines [MDA-MB-231 (triple-negative breast cancer, TNBC), MCF-7 (breast cancer), and A549 (lung cancer)]. In the MDA-MB-231 cell line, complex 1 significantly altered the cytoskeleton of the cells, reducing the density and promoting the condensation of F-actin filaments. In addition, the compound caused an increase in the percentage of cells in the fragmented DNA region (sub-G0) and induced cell death via the apoptotic pathway starting at the IC50 concentration. Taken together, the results show that complex 1 has cytotoxic and apoptotic effects on TNBC cells, which is a cell line originating from an aggressive, difficult-to-treat breast cancer.
Assuntos
Neoplasias de Mama Triplo NegativasRESUMO
BACKGROUND AND OBJECTIVES: This study aimed to determine whether there is an association between inflammation and depression taking into account the effect of several confounders, but specially plasma 25-hydroxyvitamin D (25[OH]D) levels. MATERIAL AND METHODS: A cross-sectional study was conducted on adults (n = 346) aged 60 years or older recruited from primary healthcare centres. Depression was assessed by the Geriatric Depression Scale (GDS), while plasma 25(OH)D and inflammatory cytokines were measured following routine biochemical laboratory protocols. RESULTS: Subjects were divided into two subgroups according to their depression status, and matched in their baseline conditions using random forest-based propensity scores. Both groups were rather similar in regard to most variables, apart from quality of life (p < 0.001) and plasma levels of IL-6 (p = 0.03). The overall prevalence of vitamin D deficiency was 36.3% (95% Confidence Interval [95% CI], 30.2%-42.5%), without a significant difference between depression groups (p = 0.2). A significant association was observed between GDS score and plasma IL-6 levels only among those with SF-6D score between 0.26 and 0.50 (p = 0.001). CONCLUSIONS: The association between inflammation and depression is more likely to be due to a moderation influence of quality of life rather than plasma 25(OH)D levels. However, further studies are needed to ascertain the effect of a poor quality of life leading to chronic inflammation and poor health upon longer periods of follow-up.
Assuntos
Qualidade de Vida , Deficiência de Vitamina D , Idoso , Estudos Transversais , Depressão/epidemiologia , Humanos , Inflamação , Vitamina D/análogos & derivados , Deficiência de Vitamina D/epidemiologiaRESUMO
Breast cancer metastasis is the most common cause of cancer death in women worldwide. Triple-negative breast cancers (TNBC) form a heterogeneous group of tumors that have higher relapse rates and poorer survival compared to other breast cancer subtypes. Thus, this work reports the antitumor and antimetastatic activities of a [6]-gingerol-derived semi-synthetic compound named SSi6 on MDA-MB-231 TNBC cells using xenograft models. SSi6 did not cause toxic effects in vivo as demonstrated by body weight and hematological and histological evaluations. From the orthotopic xenograft model, we demonstrated that SSi6 slows and inhibits the growth of the primary tumor, as well as prevents metastatic spontaneous progression from lymph nodes to the lungs. Moreover, a second xenograft model with resection of the primary tumor showed that SSi6 also blocks the progression of metastases from the lymph nodes to other visceral organs. Taken together, our results demonstrate that SSi6 is a promising compound to be investigated in other preclinical and clinical models to be applied as a complementary therapy for TNBC.
RESUMO
BACKGROUND: We investigated the association between inflammatory markers and muscle strength in older adults according to the presence or absence of obesity. Dynapenia is the age-related decline in muscle strength and results in negative outcomes to older adults. Accordingly, obesity is more prevalent throughout aging and is associated with comorbidities, such as type 2 diabetes, dyslipidemia and cardiovascular diseases. Both dynapenia and obesity are strongly linked to chronic inflammation, sharing common signaling pathways. METHODS: We recruited 247 older adults aged 60 or older and collected sociodemographic, anthropometric and metabolic data. Dynapenia was diagnosed according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Circulating inflammatory cytokines were measured in plasma using a multiplex panel kit. Anthropometric, sociodemographic, lipid profile, and fasting blood glucose were also assessed. RESULTS: Dynapenic participants were predominantly males (74.4%), had insufficiently active lifestyle and higher IL-10 plasma levels (0.95 pg/mL; 0.40-2.12). The prevalence of obesity was higher among non-dynapenic participants (45.3%; 95% CI, 37.7-53). In dynapenic older adults, obesity was predominant in males (53.6%) and subjects with normal muscle strength had higher serum levels of TNF-ß (0.63 pg/mL; 0.30-1.30) and lower hand-grip strength (24 kg; 20.00-28.00). Using a multivariate quantile regression analysis, we found a strong and negative association between IL-10 and muscle strength. CONCLUSIONS: This study can help to understand the association of inflammation, obesity and muscle strength to promote interventions in order to avoid or delay the negative outcomes associated with dynapenia and sarcopenia in older adults.
Assuntos
Diabetes Mellitus Tipo 2 , Sarcopenia , Idoso , Estudos Transversais , Força da Mão , Humanos , Masculino , Força Muscular , Obesidade/epidemiologia , Sarcopenia/epidemiologiaRESUMO
AIM: COVID-19 pandemic has caused extensive burden on public life and health care worldwide. This study aimed to assess circulating levels of inflammatory cytokines in adult patients who were hospitalized with COVID-19 and stratified according to age (older or younger than 65 years) aiming to explore associations between these markers of inflammation and comorbidities. METHODS: This was a cross-sectional study of 142 COVID-19 patients consecutively admitted to the University Hospital of the Federal University of São Carlos, from July to October 2020. Sociodemographic data, chronic comorbidities, and baseline NEWS2 and SOFA for clinical deterioration were obtained at hospital admission. Serum levels of inflammatory cytokines were determined by flow cytometry. RESULTS: Older adults with COVID-19 had higher serum levels of IL-6 and IL-10 as compared to those under 65 years of age (p < 0.001 and p = 0.003, respectively). IL-10 was independently associated with age (p = 0.04) and severity of the disease (p = 0.05), whereas serum levels of IL-6 were not directly associated with age (p = 0.5). The comorbidity index seems to be the main responsible for this, being significantly associated with IL-6 levels among those aged 65 and over (p = 0.007), in addition to the severity of the disease. CONCLUSIONS: Higher serum levels of IL-6 and IL-10 are associated with the severity of the disease and a higher comorbidity index among adults aged 65 and over with COVID-19. This should raise awareness of the importance of comorbidity index, rather than age, during risk stratification.
Assuntos
COVID-19/sangue , COVID-19/patologia , Interleucina-10/sangue , Interleucina-6/sangue , Índice de Gravidade de Doença , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Brasil , Comorbidade , Estudos Transversais , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/patologia , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , SARS-CoV-2/imunologia , Adulto JovemRESUMO
BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) are highly needed in clinic practice. So far, the gold standards for AD diagnosis are brain neuroimaging and beta-amyloid peptide, total tau, and phosphorylated tau in cerebrospinal fluid (CSF); however, they are not attractive for large-scale screening. Blood-based biomarkers allow an initial large-scale screening of patients under suspicion that could later be tested for the already established CSF biomarkers. To this regard, in this study, we evaluated whether plasma ADAM10 levels would be predictors of declines in cognition in community-dwelling older adults after a 3-year period follow-up. METHODS: This was a 3-year longitudinal cohort study that included 219 community-dwelling older adults. Sociodemographic, clinical, lifestyle, depressive symptoms (GDS), and cognitive data (Mini-Mental State Examination, MMSE; Clock Drawing test, CDT) were gathered. The measurement of ADAM10 plasma levels was performed using a sandwich ELISA kit. Bivariate comparisons between groups were performed using Wilcoxon-Mann-Whitney for continuous data and Pearson's chi-square tests with Yates continuity correction for categorical data. Longitudinal analyzes of changes in the MMSE scores were performed using linear mixed-effects modeling. RESULTS: Baseline MMSE scores and ADAM10 levels were significantly associated with MMSE scores on the follow-up assessment. When analyzing the interaction with time, normal MMSE scores and the ADAM10 plasma levels at baseline presented a significant and independent negative association with MMSE score values on the follow-up assessment. The analyses also showed that the predictive effect of ADAM10 plasma levels on decreasing MMSE scores on follow-up seems to be more pronounced in participants with normal MMSE, when compared with those with altered MMSE scores at baseline. CONCLUSIONS: Considering that ADAM10 increase in plasma is detected as soon as in mild cognitive impairment (MCI) patients, the results presented here may support the complementary clinical use of this biomarker, in addition to the classical AD biomarkers. Taken together, these results provide the first direct evidence that changes in ADAM10 plasma levels are predictors of cognitive worsening in older adults. Moreover, this work can shed light on the study of blood biomarkers for AD and contribute to the advancement of the area.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Proteína ADAM10 , Idoso , Doença de Alzheimer/diagnóstico , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Biomarcadores , Cognição , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Seguimentos , Humanos , Estudos Longitudinais , Proteínas de Membrana , Fragmentos de Peptídeos , Proteínas tauRESUMO
BACKGROUND: Alzheimer's disease (AD) is the main cause of dementia and it is a progressive neurogenerative disease characterized by the accumulation of neurofibrillary tangles and senile plaques. There is currently no cure; however, some treatments are available to slow down the progression of the disease, including gene therapy, which has been investigated to have great potential for the treatment of AD. OBJECTIVE: The aim of this review was to identify the efficacy of gene therapy to restore cognition in AD. METHODS: A systematic review was carried out using papers published up to May 2020 and available in the Web of Science, Scopus, and Medline/PUBMED databases. Articles were considered for inclusion if they were original researches that investigated the effects of gene therapy on cognition in AD. The methodological quality of the selected studies was evaluated using the Risk of Bias Tool for Animal Intervention Studies (SYRCLE's Rob tool) and the Jadad Scale. RESULTS: Most preclinical studies obtained positive results in improving memory and learning in mice that underwent treatment with gene therapy. On the other hand, clinical studies have obtained inconclusive results related to the delivery methods of the viral vector used in gene therapy. CONCLUSION: Gene therapy has shown a great potential for the treatment of AD in preclinical trials, but results should be interpreted with caution since preclinical studies presented limitations to predict the efficacy of the treatment outcome in humans.
Assuntos
Envelhecimento/genética , Doença de Alzheimer/terapia , Cognição , Terapia Genética/métodos , Vetores Genéticos/uso terapêutico , Animais , Progressão da Doença , Humanos , Memória , CamundongosRESUMO
This work describes the synthesis of three new ruthenium(ii) complexes with gallic acid and derivatives of the general formula [Ru(L)(dppb)(bipy)]PF6, where L = gallate (GAC), benzoate (BAC), and esterified-gallate (EGA), bipy = 2,2'-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. The complexes were characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis and IR spectroscopy, and two of them by X-ray crystallography. Cell viability assays show promising results, indicating higher cytotoxicity of the complexes in MDA-MB-231 cells, a triple-negative breast cancer (TNBC) cell line, compared with the hormone-dependent MCF-7 cell line. Studies in vitro with the MDA-MB-231 cell line showed that only Ru(BAC) and Ru(GAC) interacted with BSA. Besides that, the Ru(GAC) complex, which has a polyphenolic acid, interacted in an apo-Tf structure and function dependent manner and it was able to inhibit the formation of reactive oxygen species. Ru(GAC) was able to cause damage to the cellular cytoskeleton leading to inhibition of some cellular processes of TNBC cells, such as invasion, migration, and adhesion.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ácido Gálico/farmacologia , Piridinas/farmacologia , Rutênio/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Apoproteínas/metabolismo , Compostos de Bifenilo/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Ácido Gálico/química , Humanos , Camundongos , Picratos/química , Piridinas/química , Rutênio/química , Soroalbumina Bovina/metabolismo , Transferrina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF6 (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by 1H-31P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Fosfinas/síntese química , Fosfinas/farmacologia , Inibidores de Proteassoma/síntese química , Rutênio/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Inibidores da Topoisomerase I/síntese químicaRESUMO
In this study, HPLC-PDA-HRMS-SPE-NMR data were used for initial analysis of the CH2Cl2 fraction of an EtOH extract of the leaves of Picramnia glazioviana. The HRMS, UV, and NMR data obtained from the HPLC-PDA-HRMS-SPE-NMR analysis were used to direct semipreparative HPLC isolation toward nortriterpenoids, which resulted in the isolation of 18 new and highly oxygenated nortriterpenoids (1-3, 5-10, 12-19, and 21), named picravianes C-T. Their structures were determined on the basis of analysis of UV, HRMS, and 2D NMR spectroscopic data, including determination of the relative configuration on the basis of coupling pattern analysis and nuclear Overhauser effect correlations. The absolute configurations of compounds 7, 9, 10, 14, 15, 17, 18, 19, and 21 were assigned using electronic circular dichroism data, and the cytotoxicity of compounds 6, 10, 14, 16, 17, 18, 19, and 21 was evaluated against MDA-MB-231 triple-negative breast cancer, SKBR-3 Her2-overexpressing breast cancer, and A549 lung cancer cells lines. The isolated compounds contain a hitherto undescribed modification of the terminal backbone and/or E-ring, and a possible biosynthetic pathway for their formation is proposed.
Assuntos
Sapindaceae/química , Células A549 , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Solventes , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Six new ruthenium(ii) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P-P)(bipy)]PF6, where L = Lap or Law, P-P = 1,2'-bis(diphenylphosphino)ethane (dppe), 1,4'-bis(diphenylphosphino)butane (dppb), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2'-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cisplatin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the "normal-like" human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/química , Neoplasias de Mama Triplo Negativas/patologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Alzheimer's disease (AD) is a neurodegenerative condition that affects a large number of elderly people worldwide and has a high social and economic impact. The diagnosis of AD in early stage can significantly improve the evolution and prognosis of the disease. We report the use of A Disintegrin And Metalloprotease 10 (ADAM10) as a blood biomarker for the early diagnosis of AD. A simple, low-cost, sensitive, and disposable microfluidic platform (DµP) was developed for ADAM10 detection in plasma and cerebrospinal fluid based on electrochemical immunosensors. The assay was designed to accurately detect ADAM10 in serum, with a limit of detection of 0.35 fg/mL. ADAM10 was detected in subjects divided into cognitively healthy subjects, subjects with mild cognitive impairment, and AD patients in different disease stages. An increase in protein levels was found throughout the disease, and good DµP accuracy in differentiating individuals was observed. The DµP provided significantly better sensitivity than the well-established enzyme-linked immunosorbent assay test. ADAM10 and its detection using the DµP were proven to be an alternative tool for the early diagnosis and monitoring of AD, bringing new exciting possibilities to improve the quality of life of AD patients.
Assuntos
Doença de Alzheimer/diagnóstico , Técnicas Eletroquímicas/métodos , Imunoensaio/métodos , Microfluídica/métodos , Diagnóstico Precoce , HumanosRESUMO
In this study, half-sandwich Ru(II) complexes containing acylthiourea ligands of the general type [Ru(η6-p-cymene)(PPh3)(S)Cl]PF6 (1m-6m) and [Ru(η6-p-cymene)(PPh3)(S-O)]PF6 (1b-6b) where S/S-O = N',N'-disubstituted acylthiourea were synthesized and characterized (via elemental analyses, IR spectroscopy, 1H NMR spectroscopy, 13C{1H} NMR spectroscopy, and X-ray diffractometry), and their cytotoxic activity was evaluated. The different coordination modes of the acylthiourea ligands, monodentately via S (1m-6m) and bidentately via S,O (1b-6b), to ruthenium were modulated from different synthetic routes. The cytotoxicity of the complexes was evaluated in five human cell lines (DU-145, A549, MDA-MB-231, MRC-5, and MCF-10A) by MTT assay. The IC50 values for prostate cancer cells (2.89-7.47 µM) indicated that the complexes inhibited cell growth, but that they were less cytotoxic than cisplatin (2.00 µM). Unlike for breast cancer cells (IC50 = 0.28-0.74 µM) and lung cancer cells (IC50 = 0.51-1.83 µM), the complexes were notably more active than the reference drug, and a remarkable selectivity index (SI 4.66-19.34) was observed for breast cancer cells. Based on both the activity and selectivity, complexes 5b and 6b, as well as their respective analogous complexes in the monodentate coordination 5m and 6m, were chosen for further investigation in the MDA-MB-231 cell line. These complexes not only induced morphology changes but also were able to inhibit colony formation and migration. In addition, the complexes promoted cell cycle arrest at the sub-G1 phase inducing apoptosis. Interaction studies by viscosity measurements, gel electrophoresis, and fluorescence spectroscopy indicated that the complexes interact with the DNA minor groove and exhibit an HSA binding affinity.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Ligantes , Estrutura Molecular , Rutênio/química , Albumina Sérica Humana/metabolismo , Tioureia/metabolismoRESUMO
BACKGROUND: Blood-based biomarkers can be very useful in formulating new diagnostic and treatment proposals in the field of dementia, especially in Alzheimer's disease (AD). However, due to the influence of several factors on the reproducibility and reliability of these markers, their clinical use is still very uncertain. Thus, up-to-date knowledge about the main blood biomarkers that are currently being studied is extremely important in order to discover clinically useful and applicable tools, which could also be used as novel pharmacological strategies for the AD treatment. METHODS: A narrative review was performed based on the current candidates of blood-based biomarkers for AD to show the main results from different studies, focusing on their clinical applicability and association with AD pathogenesis. OBJECTIVE: The aim of this paper was to carry out a literature review on the major blood-based biomarkers for AD, connecting them with the pathophysiology of the disease. RESULTS: Recent advances in the search of blood-based AD biomarkers were summarized in this review. The biomarkers were classified according to the topics related to the main hallmarks of the disease such as inflammation, amyloid, and tau deposition, synaptic degeneration and oxidative stress. Moreover, molecules involved in the regulation of proteins related to these hallmarks were described, such as non-coding RNAs, neurotrophins, growth factors and metabolites. Cells or cellular components with the potential to be considered as blood-based AD biomarkers were described in a separate topic. CONCLUSION: A series of limitations undermine new discoveries on blood-based AD biomarkers. The lack of reproducibility of findings due to the small size and heterogeneity of the study population, different analytical methods and other assay conditions make longitudinal studies necessary in this field to validate these structures, especially when considering a clinical evaluation that includes a broad panel of these potential and promising blood-based biomarkers.