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1.
J Biol Inorg Chem ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722396

RESUMO

In addition to its primary oxygen-atom-transfer function, cysteamine dioxygenase (ADO) exhibits a relatively understudied anaerobic disproportionation reaction (ADO-Fe(III)-SR → ADO-Fe(II) + ½ RSSR) with its native substrates. Inspired by ADO disproportionation reactivity, we employ [Fe(tacn)Cl3] (tacn = 1,4,7-triazacyclononane) as a precursor for generating Fe(III)-thiolate model complexes in buffered aqueous media. A series of Fe(III)-thiolate model complexes are generated in situ using aqueous [Fe(tacn)Cl3] and thiol-containing ligands cysteamine, penicillamine, mercaptopropionate, cysteine, cysteine methyl ester, N-acetylcysteine, and N-acetylcysteine methyl ester. We observe trends in UV-Vis and electron paramagnetic resonance (EPR) spectra, disproportionation rate constants, and cathodic peak potentials as a function of thiol ligand. These trends will be useful in rationalizing substrate-dependent Fe(III)-thiolate disproportionation reactions in metalloenzymes.

2.
J Am Chem Soc ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38743878

RESUMO

Herein, the development of a light-mediated synthesis of functionalized indolines and tetrahydroquinolines is reported. These structural motifs are considered as highly valuable targets, attributed to their widespread occurrence in pharmaceuticals and natural products. The gold-mediated approach offers a direct route to functionalized indolines in yields of up to 81% under mild photochemical conditions. Thereby, easily accessible Boc-protected N-aryl-allylamine and homoallylamine derivatives were reacted with sp3-hybridized haloalkanes in an intermolecular cascade cyclization reaction. A broad scope of substrates, including a variety of different substituents on the aromatic backbone as well as various haloalkanes, could be utilized. Indoline derivatives, which are functionalized in position 2, are also accessible by applying ortho-allylic anilines. Moreover, the synthetic appeal was demonstrated for a total synthesis of the anti-inflammatory agent AN669 in three reaction steps in an overall yield of 64%.

3.
Mayo Clin Proc ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38661594

RESUMO

OBJECTIVE: To standardize international normalized ratio (INR) measurements and improve data integrity by enabling electronic result transmission for warfarin monitoring, two point-of-care (POC) devices were evaluated against an internal plasma INR reference method. METHODS: A multicenter study was pursued (January 24, 2022, through October 19, 2022) to compare concordance of two commercially available POC devices, Coag-Sense PT2 Meter (Coag-Sense) and CoaguChek XS Pro and Plus devices (CoaguChek), against an internal plasma INR method among patients treated with warfarin. Bias and linear regression analysis were assessed for these devices including dosing decision accuracy compared with plasma INR reference. RESULTS: Two hundred ninety-nine patients treated with warfarin across three Mayo Clinic sites agreed to participate. Atrial fibrillation (n=191, 63.9%), venous thromboembolism (n=65; 21.7%), and heart valve prosthesis (n=46; 15.4%) were common anticoagulant indications with a 2.5 INR target for 280 (93.6%) of patients. For the CoaguChek devices, 243 (81.3%) of values fell within 0.2 INR units with plasma INR referent and 285 (95.3%) within 0.4 units (R2=0.93). For the Coag-Sense device, 102 (34.1%) of values fell within 0.2 INR units and 180 (60.2%) within 0.4 INR units of plasma INR values, (R2=0.83; P<.0001). Using the plasma INR as the gold standard, appropriate dosing recommendations would have occurred for 292 (97.7%) of the CoaguChek and 244 (81.6%) of the Coag-Sense results. CONCLUSION: Compared with a plasma referent, INR values obtained from the CoaguChek devices exhibited less systematic bias compared with Coag-Sense measures. This translates to a greater percentage of concordant management decisions between POC and laboratory INR methods.

4.
Biomacromolecules ; 25(4): 2338-2347, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38499995

RESUMO

Bone is a frequent site for metastatic development in various cancer types, including breast cancer, with a grim prognosis due to the distinct bone environment. Despite considerable advances, our understanding of the underlying processes leading to bone metastasis progression remains elusive. Here, we applied a bioactive three-dimensional (3D) model capable of mimicking the endosteal bone microenvironment. MDA-MB-231 and MCF7 breast cancer cells were cultured on the scaffolds, and their behaviors and the effects of the biomaterial on the cells were examined over time. We demonstrated that close interactions between the cells and the biomaterial affect their proliferation rates and the expression of c-Myc, cyclin D, and KI67, leading to cell cycle arrest. Moreover, invasion assays revealed increased invasiveness within this microenvironment. Our findings suggest a dual role for endosteal mimicking signals, influencing cell fate and potentially acting as a double-edged sword, shuttling between cell cycle arrest and more active, aggressive states.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Materiais Biocompatíveis/farmacologia , Fenótipo , Proliferação de Células , Microambiente Tumoral/genética
5.
Neuroepidemiology ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38479366

RESUMO

INTRODUCTION: In Kenya, there is a lack of data on the number of people with dementia. In this article, we aim to estimate the number of community-dwelling older adults (aged 60 years and above) that are potentially living with dementia in rural Kenya. METHODS: Recruitment of older adults occurred through adopting a convenience approach based on the catchment areas served by trained ten Community Health Workers (CHWs). Screening was conducted using the Brief Community Screening Instrument for Dementia (CSI-D), in which prevalence ratios were reported. Regression analyses were run to understand the association between screening outcome and wellbeing, social isolation, and employment status (adjusted for age, sex, literacy, geography, and social status). RESULTS: Of the 3,546 older adults who were screened for dementia, 652 screened positive (PR = 0.18, 95%CIs 0.17 to 0.20). Back estimating screen positives based on established sensitivity and specificity of the tool against a gold standard (clinical diagnosis), yielded a prevalence of 9.4% (0.09, 95%CIs 0.08 to 0.11). Screening positive for dementia was associated with poorer quality of life (B =-0.17, p<0.001) and loneliness (B= 0.28, p<0.001). CONCLUSION: There is potentially 258,000 older adults living with dementia in Kenya, who likely have poorer outcomes. We need to encourage a timely diagnosis and develop better ways to support people living with dementia in Kenya and other resource-limited settings.

6.
Mem Cognit ; 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38180603

RESUMO

The hippocampus plays a critical role in the formation of declarative memories, and hippocampal damage leads to significant impairments in new memory formation. Drawing can serve as a form of multi-modal encoding that improves declarative memory performance relative to other multimodal encoding strategies such as writing. We examined whether, and to what extent, patients with hippocampal damage could benefit from the mnemonic strategy of drawing. Three patients with focal hippocampal damage, and one patient with both hippocampal and cortical lesions, in addition to 22 age-, sex-, and education-matched controls, were shown a list of words one at a time during encoding and instructed to either draw a picture or repeatedly write each word for 40 s. Following a brief filled delay, free recall and recognition memory for words from both encoding trial types were assessed. Controls showed enhanced recall and recognition memory for words drawn versus those that were written, an effect that was even more pronounced in patients with focal hippocampal damage. By contrast, the patient with both hippocampal and cortical lesions showed no drawing-mediated boost in either recall or recognition memory. These findings demonstrate that drawing is an effective encoding strategy, likely accruing from the engagement of extra-hippocampal processes including the integration of cortical-based motor, visual, and semantic processing, enabling more elaborative encoding.

7.
Behav Res Methods ; 56(3): 2422-2436, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37749421

RESUMO

We introduce the Individual Differences in Language Skills (IDLaS-NL) web platform, which enables users to run studies on individual differences in Dutch language skills via the Internet. IDLaS-NL consists of 35 behavioral tests, previously validated in participants aged between 18 and 30 years. The platform provides an intuitive graphical interface for users to select the tests they wish to include in their research, to divide these tests into different sessions and to determine their order. Moreover, for standardized administration the platform provides an application (an emulated browser) wherein the tests are run. Results can be retrieved by mouse click in the graphical interface and are provided as CSV file output via e-mail. Similarly, the graphical interface enables researchers to modify and delete their study configurations. IDLaS-NL is intended for researchers, clinicians, educators and in general anyone conducting fundamental research into language and general cognitive skills; it is not intended for diagnostic purposes. All platform services are free of charge. Here, we provide a description of its workings as well as instructions for using the platform. The IDLaS-NL platform can be accessed at www.mpi.nl/idlas-nl .


Assuntos
Individualidade , Internet , Humanos , Adolescente , Adulto Jovem , Adulto , Idioma , Cognição , Correio Eletrônico
8.
Cir Cir ; 91(6): 829-834, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38096859

RESUMO

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an endoscopic study in which the duodenum is observed laterally, and the bile duct is instrumented. There are several indications and complications in the procedure. OBJECTIVE: To determine the incidence of duodenal perforations, using the Stapfer classification in the Hospital Juárez de Mexico over a period of 5 years, as well as the management implemented in such cases. METHOD: The study was carried out at the Hospital Juárez de Mexico of the Ministry of Health. All patients who underwent ERCP between January 1, 2017, to May 30, 2022 were included. RESULTS: 485 ERCP were performed in the study period. Incidence of 1.6% post-ERCP duodenal perforation. The average age of the subjects 56.37 years. In-hospital stay of post-ERCP perforations averaged 9.37 days. The time of the endoscopic study at the time of the surgical procedure is 10 h on average. CONCLUSIONS: Post-ERCP duodenal perforation is a complication that occurs with a low incidence, it tends to increase the number of days of in-hospital stay and increases morbimortality of patients; therefore, it is important to be always alert.


ANTECEDENTES: La colangiopancreatografía retrógrada endoscópica (CPRE) es un estudio endoscópico en el cual se observa lateralmente el duodeno y se instrumenta la vía biliar. Existen diversas indicaciones y complicaciones en el procedimiento. OBJETIVO: Determinar la incidencia de perforaciones duodenales utilizando la clasificación Stapfer para ubicación anatómica en el Hospital Juárez de México en un periodo de 5 años, así como el manejo implementado en dichos casos. MÉTODO: El estudio se realizó en el Hospital Juárez de México de la Secretaría de Salud. Se incluyeron todos los pacientes sometidos a CPRE entre el 1 de enero de 2017 y el 30 de mayo de 2022. RESULTADOS: Se realizaron 485 CPRE en el periodo de estudio. Hubo una incidencia del 1.6% de perforación duodenal post-CPRE. El promedio de edad de los sujetos fue de 56.37 años. La estancia hospitalaria de los pacientes con perforación post-CPRE fue en promedio de 9.37 días. El tiempo del estudio endoscópico al momento de realizar el procedimiento quirúrgico fue de 10 h en promedio. CONCLUSIONES: La perforación duodenal post-CPRE es una complicación que ocurre con una baja incidencia, suele aumentar los días de estancia intrahospitalaria y aumenta la morbimortalidad de los pacientes, y por ello es importante estar siempre alerta.


Assuntos
Úlcera Duodenal , Perfuração Intestinal , Úlcera Péptica Perfurada , Humanos , Pessoa de Meia-Idade , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , México/epidemiologia , Perfuração Intestinal/epidemiologia , Perfuração Intestinal/etiologia , Perfuração Intestinal/cirurgia , Estudos Retrospectivos , Duodeno/cirurgia , Úlcera Duodenal/complicações
9.
BMC Infect Dis ; 23(1): 450, 2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37415105

RESUMO

BACKGROUND: Disseminated sporotrichosis is a severe opportunistic infection that often affects immunocompromised patients after a cutaneous inoculation. Here we present a rare case of disseminated sporotrichosis discovered as a solitary intramedullary thoracic spinal cord lesion in an immunocompetent patient. CASE DESCRIPTION: A 37-year-old man presented with progressive lower limb weakness and sensory changes over 1 week. A spinal magnetic resonance imaging (MRI) revealed a contrast-enhancing intramedullary lesion centered at T10. The patient was afebrile and reported no history of trauma or cutaneous lesions. The lesion was unresponsive to a trial of corticosteroids. A thoracic laminectomy was performed and a biopsy obtained. A cutaneous lesion on the arm was concurrently discovered, which was also biopsied. Both the skin and spinal cord biopsies showed Sporothrix schenckii by macroscopic and microscopic morphology which were later confirmed by MALDI-TOF mass spectrometry. CONCLUSION: This is a rare case of intramedullary disseminated sporotrichosis affecting the central nervous system of an immunocompetent patient. This unusual presentation should be taken into consideration when such intramedullary lesions are encountered.


Assuntos
Sporothrix , Esporotricose , Masculino , Humanos , Adulto , Esporotricose/diagnóstico , Esporotricose/tratamento farmacológico , Esporotricose/patologia , Antifúngicos/uso terapêutico , Pele/patologia , Biópsia
10.
ChemMedChem ; 18(19): e202300265, 2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37421174

RESUMO

In an effort to further investigate previously observed activity of indolyl sulfonamides towards pancreatic cancer cell lines, a library of 44 compounds has been synthesized. The biological activity of the compounds has been determined using two different screening assay techniques against 7 pancreatic cancer cell lines and 9 non-pancreatic cancer cell lines. In the first assay, the cytotoxicity of the compounds was evaluated using a traditional (48 hour compound exposure) method. An in silico investigation was conducted to determine if the compounds might be inducing cell death by inhibiting the S100A2-p53 protein-protein interaction. In the second assay, the potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (1-2 hour compound exposure) method. IC50 values of the hit compounds were obtained and four compounds displayed sub-micromolar potency against PANC-1 cells. The investigation has provided several compounds that display selective in vitro activity toward pancreatic cancer that warrant further development.


Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proliferação de Células , Linhagem Celular Tumoral
11.
Metallomics ; 15(6)2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37193665

RESUMO

ZnT1 is a major zinc transporter that regulates cellular zinc homeostasis. We have previously shown that ZnT1 has additional functions that are independent of its activity as a Zn2+ extruder. These include inhibition of the L-type calcium channel (LTCC) through interaction with the auxiliary ß-subunit of the LTCC and activation of the Raf-ERK signaling leading to augmented activity of the T-type calcium channel (TTCC). Our findings indicate that ZnT1 increases TTCC activity by enhancing the trafficking of the channel to the plasma membrane. LTCC and TTCC are co-expressed in many tissues and have different functions in a variety of tissues. In the current work, we investigated the effect of the voltage-gated calcium channel (VGCC) ß-subunit and ZnT1 on the crosstalk between LTCC and TTCC and their functions. Our results indicate that the ß-subunit inhibits the ZnT1-induced augmentation of TTCC function. This inhibition correlates with the VGCC ß-subunit-dependent reduction in ZnT1-induced activation of Ras-ERK signaling. The effect of ZnT1 is specific, as the presence of the ß-subunit did not change the effect of endothelin-1 (ET-1) on TTCC surface expression. These findings document a novel regulatory function of ZnT1 serving as a mediator in the crosstalk between TTCC and LTCC. Overall, we demonstrate that ZnT1 binds and regulates the activity of the ß-subunit of VGCC and Raf-1 kinase and modulates surface expression of the LTCC and TTCC catalytic subunits, consequently modulating the activity of these channels.


Assuntos
Canais de Cálcio Tipo L , Canais de Cálcio Tipo T , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo T/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Animais , Xenopus
12.
Dementia (London) ; 22(5): 1027-1037, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37036049

RESUMO

BACKGROUND: In Kenya, there is lack of evidence on existing dementia care pathways, with minimal or no presentation for dementia-related symptoms in health care settings. Understanding the services available for people with dementia as well as how communities access the services could offer a practical pattern for policy makers to identify strategies that encourage early detection, care and support for people with dementia and their families. OBJECTIVES: To elucidate initial responses of individuals and their families to dementia and challenges encountered in help seeking through care pathways to inform dementia care-related policies and practice. METHODS: The Strengthening Responses to dementia in Developing Countries (STRiDE) Kenya team adapted case vignettes (brief hypothetical stories meant to elicit responses on how the characters would behave) developed by the entire STRiDE team. A total of 29 stakeholders were then asked to provide feedback on the completed vignettes and summarize a common pathway to dementia care in Kenya while using the proposed case vignettes. FINDINGS: We found four initial responses to dementia suspicion in Kenya where individuals:(i) Perceive symptoms as normal part of ageing, (ii) Consult a spiritual or traditional healer, (iii) Visit a private clinic or primary health care facilities, or (iv) No action taken. These were the first points within the care pathways which determined the care trajectory the person with dementia would follow. CONCLUSIONS: Identification of dementia care pathways could form a basis for improving the way communities perceive dementia etiology and establish standard pathways to care whilst ensuring that some pathways do not further pose an impediment to care and treatment for dementia.


Assuntos
Demência , Humanos , Demência/terapia , Quênia , Procedimentos Clínicos , Formulação de Políticas , Encaminhamento e Consulta
13.
Clin Exp Metastasis ; 40(2): 125-135, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37038009

RESUMO

A participant in key developmental processes, the adhesion glycoprotein CD44 is also expressed in several types of malignancies and can promote metastasis. In addition, the expression of CD44 isoforms in different types of cancer such as prostate and breast cancers may facilitate bone metastases by enhancing tumorigenicity, osteomimicry, cell migration, homing to bone, and anchorage within the bone specialized domains. Moreover, there is evidence that the CD44-ICD fragments in breast cancer cells may promote the cells' osteolytic nature. Yet the mechanisms by which CD44 and its downstream effectors promote the establishment of these cells within the bone are not fully elucidated. In this review, we summarize the current data on the roles played by CD44 in cancer progression and bone metastasis and the possible effects of its interaction with the different components of the bone marrow milieu.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Masculino , Humanos , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Osso e Ossos/patologia , Movimento Celular , Receptores de Hialuronatos , Metástase Neoplásica/patologia
14.
Antibiotics (Basel) ; 11(12)2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36551410

RESUMO

Klebsiella pneumoniae is a multidrug-resistant opportunistic human pathogen related to various infections. As such, synthetic peptides have emerged as potential alternative molecules. Mo-CBP3-PepI has presented great activity against K. pneumoniae by presenting an MIC50 at a very low concentration (31.25 µg mL-1). Here, fluorescence microscopy and proteomic analysis revealed the alteration in cell membrane permeability, ROS overproduction, and protein profile of K. pneumoniae cells treated with Mo-CBP3-PepI. Mo-CBP3-PepI led to ROS overaccumulation and membrane pore formation in K. pneumoniae cells. Furthermore, the proteomic analysis highlighted changes in essential metabolic pathways. For example, after treatment of K. pneumoniae cells with Mo-CBP3-PepI, a reduction in the abundance of protein related to DNA and protein metabolism, cytoskeleton and cell wall organization, redox metabolism, regulation factors, ribosomal proteins, and resistance to antibiotics was seen. The reduction in proteins involved in vital processes for cell life, such as DNA repair, cell wall turnover, and protein turnover, results in the accumulation of ROS, driving the cell to death. Our findings indicated that Mo-CBP3-PepI might have mechanisms of action against K. pneumoniae cells, mitigating the development of resistance and thus being a potent molecule to be employed in producing new drugs against K. pneumoniae infections.

15.
Mar Drugs ; 20(12)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36547934

RESUMO

Metal-polysaccharides have recently raised significant interest due to their multifunctional bioactivities. The antimicrobial activity of a complex of Cu2O with the sulfated polysaccharide (PS) of the marine red microalga Porphyridium sp. was previously attributed to spikes formed on the complex surface (roughness). This hypothesis was further examined here using other Cu-PS complexes (i.e., monovalent-Cu2O, CuCl and divalent-CuO, CuCl2). The nanostructure parameters of the monovalent complexes, namely, longer spikes (1000 nm) and greater density (2000-5000 spikes/µm2) were found to be related to the superior inhibition of microbial growth and viability and biofilm formation. When Escherichia coli TV1061, used as a bioluminescent test organism, was exposed to the monovalent Cu-PS complexes, enhanced bioluminescence accumulation was observed, probably due to membrane perforation by the spikes on the surface of the complexes and consequent cytoplasmic leakage. In addition, differences were found in the surface chemistry of the monovalent and divalent Cu-PS complexes, with the monovalent Cu-PS complexes exhibiting greater stability (ζ-potential, FTIR spectra, and leaching out), which could be related to spike formation. This study thus supports our hypothesis that the spikes protruding from the monovalent Cu-PS surfaces, as characterized by their aspect ratio, are responsible for the antimicrobial and antibiofilm activities of the complexes.


Assuntos
Anti-Infecciosos , Microalgas , Porphyridium , Microalgas/química , Metais , Anti-Infecciosos/farmacologia , Polissacarídeos/farmacologia , Polissacarídeos/química , Cobre/farmacologia , Cobre/química
16.
Pathogens ; 11(9)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36145427

RESUMO

Staphylococcus aureus is a human pathogen known to be resistant to antibiotics since the mid-20th century and is constantly associated with hospital-acquired infections. S. aureus forms biofilms, which are complex surface-attached communities of bacteria held together by a self-produced polymer matrix consisting of proteins, extracellular DNA, and polysaccharides. Biofilms are resistance structures responsible for increasing bacterial resistance to drugs by 1000 times more than the planktonic lifestyle. Therefore, studies have been conducted to discover novel antibacterial molecules to prevent biofilm formation and/or degrade preformed biofilms. Synthetic antimicrobial peptides (SAMPs) have appeared as promising alternative agents to overcome increasing antibiotic resistance. Here, the antibiofilm activity of eight SAMPs, in combination with the antibiotic ciprofloxacin, was investigated in vitro. Biofilm formation by S. aureus was best inhibited (76%) by the combination of Mo-CBP3-PepIII (6.2 µg mL-1) and ciprofloxacin (0.39 µg mL-1). In contrast, the highest reduction (60%) of the preformed biofilm mass was achieved with RcAlb-PepII (1.56 µg mL-1) and ciprofloxacin (0.78 µg mL-1). Fluorescence microscopy analysis reinforced these results. These active peptides formed pores in the cellular membrane of S. aureus, which may be related to the enhanced ciprofloxacin's antibacterial activity. Our findings indicated that these peptides may act with ciprofloxacin and are powerful co-adjuvant agents for the treatment of S. aureus infections.

17.
Pharmaceutics ; 14(8)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36015304

RESUMO

Cryptococcus neoformans is a human-pathogenic yeast responsible for pneumonia and meningitis, mainly in patients immunocompromised. Infections caused by C. neoformans are a global health concern. Synthetic antimicrobial peptides (SAMPs) have emerged as alternative molecules to cope with fungal infections, including C. neoformans. Here, eight SAMPs were tested regarding their antifungal potential against C. neoformans and had their mechanisms of action elucidated by fluorescence and scanning electron microscopies. Five SAMPs showed an inhibitory effect (MIC50) on C. neoformans growth at low concentrations. Fluorescence microscope (FM) revealed that SAMPs induced 6-kDa pores in the C. neoformans membrane. Inhibitory assays in the presence of ergosterol revealed that some peptides lost their activity, suggesting interaction with it. Furthermore, FM analysis revealed that SAMPs induced caspase 3/7-mediated apoptosis and DNA degradation in C. neoformans cells. Scanning Electron Microscopy (SEM) analysis revealed that peptides induced many morphological alterations such as cell membrane, wall damage, and loss of internal content on C. neoformans cells. Our results strongly suggest synthetic peptides are potential alternative molecules to control C. neoformans growth and treat the cryptococcal infection.

18.
Microsc Microanal ; : 1-8, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35638222

RESUMO

The advances in machine learning (ML) software availability, efficiency, and friendliness, combined with the increase in the computation power of personal computers, are harnessed to rapidly and (relatively) effortlessly analyze time-lapse image series of adherent cell cultures, taken with phase-contrast microscopy (PCM). Since PCM is arguably the most widely used technique to visualize adherent cells in a label-free, noninvasive, and nondisruptive manner, the ability to easily extract quantitative information on the area covered by cells, should provide a valuable tool for investigation. We demonstrate two cases, in one we monitor the shrinking of cells in response to a toxicant, and in the second we measure the proliferation curve of mesenchymal stem cells (MSCs).

19.
Rev Neurol (Paris) ; 178(5): 441-449, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35491247

RESUMO

Huntington's disease is a rare, severe, and inherited neurodegenerative disorder that affects young adults. To date, there is no treatment to stop its progression. The primary atrophy of the striatum in HD, is limited in space and centrally focalised in the brain and thus constitutes a good candidate for graft. Therefore, transplantation of foetal cells from the ganglionic eminence, the germinal zone of the striatum, has the potential to restore disrupted fronto-cortical circuits and corresponding clinical functions. The international Multicentric intracerebral Grafting in Huntington's disease trial was not as successful as two pilot trials (Créteil and London) which showed promising results in the 2000s, displaying stabilisation/recovery of symptoms in some patients. A point-by-point comparison of the differences between MIG-HD and the pilot trial from Créteil in which similar data are available provides lessons on the grafting procedure and allows for strategic thinking before embarking on future trials. MIG-HD demonstrated the existence of intracerebral alloimmunisation leading to acute or chronic graft rejection into the brain and showed the limitations of surgical standardisation and immunosuppression. It has also improved the safety of the procedure and provided guidance for the follow-up of future patients. Indeed, even if disease modifiers treatments are currently the focus of intense research, they may not stop or slow the progression of the disease sufficiently, or even be administered in all patients, to prevent brain atrophy in all cases. Although disease-modifying therapies are currently the subject of intense research, they may not stop or slow disease progression sufficiently, or may not be given to all patients to prevent brain atrophy. A combination with intracerebral transplantation to repair the damaged structures may thus prove beneficial. Altogether, pursuing research in intracerebral transplantation remains necessary.


Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Atrofia , Encéfalo/patologia , Encéfalo/cirurgia , Corpo Estriado/transplante , Humanos , Doença de Huntington/cirurgia
20.
J Mater Chem B ; 10(35): 6688-6697, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35583238

RESUMO

Cadherins are cell-surface proteins that mediate cell-cell adhesion. By regulating their grip formation and strength, cadherins play a pivotal role during normal tissue morphogenesis and homeostasis of multicellular organisms. However, their dysfunction is associated with cell migration and proliferation, cancer progression and metastasis. The conserved amino acid sequence His-Ala-Val (HAV) in the extracellular domain of cadherins is implicated in cadherin-mediated adhesion and migration. Antagonists of cadherin adhesion such as monoclonal antibodies and small molecule inhibitors based on HAV peptides, are of high therapeutic value in cancer treatment. However, antibodies are not stable outside their natural environment and are expensive to produce, while peptides have certain limitations as a drug as they are prone to proteolysis. Herein, we propose as alternative, a synthetic antibody based on molecularly imprinted polymer nanogels (MIP-NGs) to target the HAV domain. The MIP-NGs are biocompatible, have high affinity for N-cadherin and inhibit cell adhesion and migration of human cervical adenocarcinoma (HeLa) cells, as demonstrated by cell aggregation and Matrigel invasion assays, respectively. The emergence of MIPs as therapeutics for fighting cancer is still in its infancy and this novel demonstration reinforces the fact that they have a rightful place in cancer treatment.


Assuntos
Caderinas , Polímeros Molecularmente Impressos , Anticorpos Monoclonais , Caderinas/metabolismo , Adesão Celular , Humanos , Proteínas de Membrana , Nanogéis , Peptídeos/química
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