RESUMO
Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.
Assuntos
Apoptose , Morte Celular Autofágica , Neoplasias Hepáticas , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Células Hep G2 , Morte Celular Autofágica/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/químicaRESUMO
Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs.
RESUMO
Although some studies have shown neuroimaging and neuropsychological alterations in post-COVID-19 patients, fewer combined neuroimaging and neuropsychology evaluations of individuals who presented a mild acute infection. Here we investigated cognitive dysfunction and brain changes in a group of mildly infected individuals. We conducted a cross-sectional study of 97 consecutive subjects (median age of 41 years) without current or history of psychiatric symptoms (including anxiety and depression) after a mild infection, with a median of 79 days (and mean of 97 days) after diagnosis of COVID-19. We performed semi-structured interviews, neurological examinations, 3T-MRI scans, and neuropsychological assessments. For MRI analyses, we included a group of non-infected 77 controls. The MRI study included white matter (WM) investigation with diffusion tensor images (DTI) and functional connectivity with resting-state functional MRI (RS-fMRI). The patients reported memory loss (36%), fatigue (31%) and headache (29%). The quantitative analyses confirmed symptoms of fatigue (83% of participants), excessive somnolence (35%), impaired phonemic verbal fluency (21%), impaired verbal categorical fluency (13%) and impaired logical memory immediate recall (16%). The WM analyses with DTI revealed higher axial diffusivity values in post-infected patients compared to controls. Compared to controls, there were no significant differences in the functional connectivity of the posterior cingulum cortex. There were no significant correlations between neuropsychological scores and neuroimaging features (including DTI and RS-fMRI). Our results suggest persistent cognitive impairment and subtle white matter abnormalities in individuals mildly infected without anxiety or depression symptoms. The longitudinal analyses will clarify whether these alterations are temporary or permanent.
Assuntos
Encefalopatias , COVID-19 , Disfunção Cognitiva , Substância Branca , Humanos , Adulto , Imagem de Tensor de Difusão/métodos , Estudos Transversais , COVID-19/complicações , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Encéfalo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Transtornos da Memória , Fadiga/etiologiaRESUMO
The objectives of this experiment were to evaluate the effects of increasing levels of orange molasses in replacement of flint corn grain in high-concentrate diets on dry matter intake (DMI), average daily gain (ADG), and feed efficiency (FE) of feedlot lambs. Thirty male lambs without defined racial pattern (30.3 ± 5.3 kg of initial BW; mean ± SD) were used in a randomized complete block design with 10 blocks and 3 treatments. The treatments were defined by partial replacement of flint corn by orange molasses in the diet with 90% of concentrate and 10% of Cynodon spp. hay, as follows: 0OM-control diet without orange molasses; 20OM-20% of orange molasses replacing flint corn; and 40OM-40% of orange molasses replacing flint corn (DM basis). The experiment lasted 72 days divided into 3 subperiods, with 1 subperiod of 16 days and 2 subperiods of 28 days. Animals were weighed after a 16-h fast on days 1, 16, 44, and 72 of the experimental periods to determine the ADG and FE. The DMI, ADG, and FE showed an interaction between treatments and experimental periods. The DMI in the first period decreased linearly (P < 0.01); in the third period, there was no effect of treatments (P > 0.05) on DMI. The ADG decreased linearly (P < 0.01) in the first period as the orange molasses increased. Otherwise, in the third period, ADG increased linearly (P = 0.05) as flint corn was replacement by orange molasses. The FE showed an interaction between treatment and period (P = 0.09). The first period had a decreased linear effect; in the third period, there was a trend (P = 0.07) of increased linear effect. There was no difference between the diets regarding the final BW of the lambs. In conclusion, the orange molasses can replace up to 40% of flint corn in diets for feedlot lambs without affecting final BW. However, it is important to consider the adaptation time proved to be very important for better use of orange molasses as a source of energy in diets for lambs.
Assuntos
Citrus sinensis , Ovinos , Animais , Masculino , Brasil , Melaço , Dieta/veterinária , Zea mays , Minerais , Carneiro Doméstico , Ração Animal/análiseRESUMO
The causes of the neurodegenerative processes in Alzheimer's disease (AD) are not completely known. Recent studies have shown that white matter (WM) damage could be more severe and widespread than whole-brain cortical atrophy and that such damage may appear even before the damage to the gray matter (GM). In AD, Amyloid-beta (Aß42 ) and tau proteins could directly affect WM, spreading across brain networks. Since hippocampal atrophy is common in the early phase of disease, it is reasonable to expect that hippocampal volume (HV) might be also related to WM integrity. Our study aimed to evaluate the integrity of the whole-brain WM, through diffusion tensor imaging (DTI) parameters, in mild AD and amnestic mild cognitive impairment (aMCI) due to AD (with Aß42 alteration in cerebrospinal fluid [CSF]) in relation to controls; and possible correlations between those measures and the CSF levels of Aß42 , phosphorylated tau protein (p-Tau) and total tau (t-Tau). We found a widespread WM alteration in the groups, and we also observed correlations between p-Tau and t-Tau with tracts directly linked to mesial temporal lobe (MTL) structures (fornix and hippocampal cingulum). However, linear regressions showed that the HV better explained the variation found in the DTI measures (with weak to moderate effect sizes, explaining from 9% to 31%) than did CSF proteins. In conclusion, we found widespread alterations in WM integrity, particularly in regions commonly affected by the disease in our group of early-stage disease and patients with Alzheimer's disease. Nonetheless, in the statistical models, the HV better predicted the integrity of the MTL tracts than the biomarkers in CSF.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Imagem de Tensor de Difusão , Encéfalo/patologia , Biomarcadores/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Atrofia/patologia , Disfunção Cognitiva/metabolismoRESUMO
A hanseníase é uma doença crônica, infectocontagiosa, de notificação compulsória e investigação obrigatória no Brasil, de evolução lenta, causada pelo bacilo Mycobacterium leprae que acomete predominantemente pele e nervos periféricos causando incapacidades funcionais permanentes de diversos graus, além de ser uma patologia ainda cercada por estigma e discriminação social. O objetivo do artigo consiste em avaliar o perfil epidemiológico da hanseníase no Estado do Rio Grande do Norte entre 2018 a 2022, estado que ocupa, atualmente, o 3° lugar a nível nacional de registro geral de casos de hanseníase. Trata-se de um estudo epidemiológico, descritivo, retrospectivo e de abordagem quantitativa, com base em dados obtidos no Departamento de Informática do Sistema Único de Saúde (DATASUS) e analisados com auxílio do software livre Jamovi 2.3.21 solid. O perfil epidemiológico da hanseníase no período de 2018 a 2022, no Estado do Rio Grande do Norte, apresentou predomínio pelo sexo feminino, acometendo adultos entre 50 a 69 anos de idade, com registro ignorado ou em branco no grau de escolaridade, predominando a forma multibacilar do tipo Virchowiana, causando grau 0 de incapacidade e a grande parte dos casos evoluindo para a cura. Portanto, faz-se relevante conhecer melhor o perfil epidemiológico e a realidade de cada município, visto que é uma patologia fortemente relacionada a condições econômicas, sociais e ambientais desfavoráveis passíveis de intervenção.
Leprosy is a chronic, contagious infectious disease, compulsorily notifiable and compulsory research in Brazil, of slow evolution, caused by the bacillus Mycobacterium leprae that predominantly affects skin and peripheral nerves causing permanent functional impairments of various degrees, besides being a pathology still surrounded by stigma and social discrimination. The objective of the article is to evaluate the epidemiological profile of leprosy in the State of Rio Grande do Norte between 2018 and 2022, which currently occupies the 3rd place at the national level of general registration of cases of leprosy. This is an epidemiological, descriptive, retrospective and quantitative approach study, based on data obtained in the Department of Information Technology of the Unified Health System (DATASUS) and analyzed with the help of free software Jamovi 2.3.21 solid. The epidemiological profile of leprosy in the period from 2018 to 2022, in the state of Rio Grande do Norte, showed predominance by the female sex, affecting adults between 50 and 69 years of age, with ignored or blank registration in the level of schooling, predominating the multibacillary form of the Virchowiana type, causing grade 0 disability and the great majority of cases evolving to cure. Therefore, it is important to know better the epidemiological profile and reality of each municipality, since it is a pathology strongly related to unfavorable economic, social and environmental conditions that can intervene.
La Hanseniasis es una enfermedad crónica, una enfermedad contagiosa, una notificación obligatoria e investigación obligatoria en Brasil, de evolución lenta, causada por el bacilo Mycobacterium leprae, que ataca predominantemente la piel y los nervios periféricos, causando discapacidades funcionales permanentes de diversos grados, además de ser una enfermedad aún rodeada de estigma y discriminación social. El propósito del artículo es evaluar el perfil epidemiológico de la lepra en el estado de Río Grande del Norte entre 2018 y 2022, un estado que actualmente ocupa el tercer lugar en el registro general nacional de casos de lepra. Se trata de un estudio de enfoque epidemiológico, descriptivo, retrospectivo y cuantitativo basado en datos obtenidos del Departamento de Datos del Sistema de Salud Pública (DATASUS) y analizado con la ayuda del software sólido Jamovi 2.3.21 libre. El perfil epidemiológico de la lepra en el período 2018-2022, en el estado de Rio Grande do Norte, mostró predominio del sexo femenino, atacando a adultos de 50 a 69 años, con un registro desconocido o en blanco en el grado de escolaridad, predominando en la forma multibacible del tipo Virchowiana, causando un grado de discapacidad y el gran número de casos. evolucionando hacia la curación. Por lo tanto, es importante conocer mejor el perfil epidemiológico y la realidad de cada municipio, ya que se trata de una enfermedad que está fuertemente relacionada con condiciones económicas, sociales y ambientales desfavorables que pueden ser intervenidas.
RESUMO
Oxidative stress plays a central role in the pathophysiology of melanoma. Curcumin (CUR) is a polyphenolic phytochemical that stimulates reactive oxygen species (ROS) production, while disulfiram (DSS) is a US FDA-approved drug for the treatment of alcoholism that can act by inhibiting the intracellular antioxidant system. Therefore, we hypothesized that they act synergistically against melanoma cells. Herein, we aimed to study the antitumor potential of the combination of CUR with DSS in B16-F10 melanoma cells using in vitro and in vivo models. The cytotoxic effects of different combination ratios of CUR and DSS were evaluated using the Alamar Blue method, allowing the production of isobolograms. Apoptosis detection, DNA fragmentation, cell cycle distribution, and mitochondrial superoxide levels were quantified by flow cytometry. Tumor development in vivo was evaluated using C57BL/6 mice bearing B16-F10 cells. The combinations ratios of 1:2, 1:3, and 2:3 showed synergic effects. B16-F10 cells treated with these combinations showed improved apoptotic cell death and DNA fragmentation. Enhanced mitochondrial superoxide levels were observed at combination ratios of 1:2 and 1:3, indicating increased oxidative stress. In vivo tumor growth inhibition for CUR (20 mg/kg), DSS (60 mg/kg), and their combination were 17.0%, 19.8%, and 28.8%, respectively. This study provided data on the potential cytotoxic activity of the combination of CUR with DSS and may provide a useful tool for the development of a therapeutic combination against melanoma.
Assuntos
Antineoplásicos , Curcumina , Melanoma Experimental , Camundongos , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Dissulfiram/farmacologia , Linhagem Celular Tumoral , Superóxidos/metabolismo , Camundongos Endogâmicos C57BL , Melanoma Experimental/metabolismo , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estresse OxidativoRESUMO
Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.
Assuntos
Encéfalo , COVID-19 , Viroses do Sistema Nervoso Central , SARS-CoV-2 , Astrócitos/patologia , Astrócitos/virologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/patologia , Viroses do Sistema Nervoso Central/etiologia , Viroses do Sistema Nervoso Central/patologia , Humanos , Síndrome de COVID-19 Pós-AgudaRESUMO
Duguetia A. St. Hill (Annonaceae) is recognized as one of the major genera with approximately 100 species, 67 of which are found in Brazil (29 of those are endemic). They are arboreal species with edible fruits known as "pindaíba", "pindaíva" "pinha", and "envira" in Brazil. Many Duguetia species, in particular, have been used in traditional medicine to treat renal colic, stomachache, rheumatism, cough, toothache, muscle pain, fever, gastrointestinal pain, and breathing difficulties. In this study, we reviewed the chemical constituents and pharmacological properties of essential oils (EOs) from Duguetia species. A total of 12 species were found, along with their EO chemical constituents and bioactivities. Bicyclogermacrene, humulene epoxide II, spathulenol, germacrene D, caryophyllene oxide, viridiflorene, α-pinene, ß-caryophyllene, and ß-pinene were the main chemical constituents reported. The pharmacological effects of Duguetia species EOs included anti-inflammatory, antinociceptive, antibacterial, antifungal, antioxidant, anti-trypanosoma, cytotoxic and antitumor properties. This information adds to our understanding of the potential of the EOs of Duguetia species.
Assuntos
Annonaceae , Óleos Voláteis , Annonaceae/química , Antibacterianos/farmacologia , Antifúngicos , Brasil , Óleos Voláteis/química , Óleos Voláteis/farmacologiaRESUMO
Background: Although several studies have emphasized the association between epilepsy and psychiatric disorders, fewer have investigated the impact of epilepsy on caregivers' emotional status, mainly in adult people with epilepsy (PWE). Here we investigated depressive symptoms, suicidal ideation, and anxiety symptoms in a large group of adult PWE and their caregivers. Methods: We analyzed symptoms of depression [with the Beck Depression Inventory-II (BDI-II)], suicidal ideation (with BDI-II item 9), and anxiety symptoms (with the Beck Anxiety Inventory) in a large group of adult PWE [N = 548 (60% women; median age 41)] and caregivers [N = 191 (72% women; median age 47)] from a Brazilian tertiary center, considering sociodemographic and clinical aspects. We also applied the Liverpool Adverse Events Profile to assess anti-seizure drugs adverse events. Results: While the presence (p = 0.026) (and intensity, p = 0.007) of depressive symptoms and suicidal ideation (p = 0.02) were higher in PWE compared to caregivers, the proportion of clinical anxiety symptoms (p = 0.32) (and the intensity, p = 0.13) was similar in both groups. Although the rates of suicidal ideation were higher in focal epilepsy (20%), both generalized genetic epilepsy and caregivers also presented elevated frequencies (11%) of suicidal ideation. The analyses of 120 patient-caregiver dyads revealed that the intensity of depressive symptoms in PWE (but not anxiety) correlated with the intensity of depressive (r = 0.35; p < 0.001) and anxiety (r = 0.25; p = 0.01) symptoms in their caregivers. In the multivariate analyses of PWE, focal epilepsy (compared to GGE) was associated with clinical depressive symptoms (odds ratio, OR 2.1) and suicidal ideation (OR 3.2), while recurrent seizures (compared to the seizure-free group) were associated with suicidal ideation (OR 2.6) and anxiety symptoms (OR 2.1). Also, caregivers with anxiety symptoms were 8 times more likely to exhibit depressive symptoms, and those with depressive symptoms were 8 times more likely to present anxiety symptoms. Conclusion: Our study suggests that specific attention for the caregivers' mental health is as essential as PWE. There is an urgent need for more studies involving caregivers to identify their emotional distress and provide adequate treatment.