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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167174, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38631406

RESUMO

Mature oligodendrocytes (OLs) arise from oligodendrocyte precursor cells that, in case of demyelination, are recruited at the lesion site to remyelinate the axons and therefore restore the transmission of nerve impulses. It has been widely documented that exogenously administered steroid molecules are potent inducers of myelination. However, little is known about how neurosteroids produced de novo by OLs can impact this process. Here, we employed a human OL precursor cell line to investigate the role of de novo neurosteroidogenesis in the regulation of OLs differentiation, paying particular attention to the 18 kDa Translocator Protein (TSPO) which controls the rate-limiting step of the neurosteroidogenic process. Our results showed that, over the time of OL maturation, the availability of cholesterol, which is the neurosteroidogenesis initial substrate, and key members of the neurosteroidogenic machinery, including TSPO, were upregulated. In addition, OLs differentiation was impaired following neurosteroidogenesis inhibition and TSPO silencing. On the contrary, TSPO pharmacological stimulation promoted neurosteroidogenic function and positively impacted differentiation. Collectively, our results suggest that de novo neurosteroidogenesis is actively involved in the autocrine and paracrine regulation of human OL differentiation. Moreover, since TSPO was able to promote OL differentiation through a positive modulation of the neurosteroid biosynthetic process, it could be exploited as a promising target to tackle demyelinating diseases.

2.
Int J Mol Sci ; 25(7)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38612542

RESUMO

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation's impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios.


Assuntos
Epilepsia , Viroses , Vírus , Humanos , Anticonvulsivantes/uso terapêutico , Doenças Neuroinflamatórias , Viroses/complicações , Viroses/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Biomarcadores
4.
Toxicon ; 241: 107682, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38460605

RESUMO

Hemorrhagic stroke is a severe complication reported in cases of Bothrops atrox snakebite envenomation. We report an unusual case of a patient who evolved with an intracranial hemorrhagic stroke and was in a coma for more than five years in a tertiary hospital located in Manaus, Amazonas. 52-year-old man, carpenter, resident in the rural area of the municipality of Tabatinga, located 1106 km from Manaus, capital of Amazonas, Brazil, victim of an accident involving Bothrops atrox evolution with cardiorespiratory arrest, acute kidney injury and hemorrhagic stroke. After 43 days of hospitalization in the ICU, he was transferred to the ward, without contact with the environment and family, sent for home treatment, however, without acceptance by family members. During a long hospital stay for a period of 6 years, totally dependent on special care, in a flexed position, using a tracheostomy and mechanical ventilation, diagnosed and treated for hospital infections throughout his hospitalization, he died due to bacterial pneumonia. Losses of autonomy can result in an individual being completely disconnected from social life - a "social death before physical death".


Assuntos
Bothrops , Venenos de Crotalídeos , Acidente Vascular Cerebral Hemorrágico , Mordeduras de Serpentes , Masculino , Animais , Humanos , Pessoa de Meia-Idade , Mordeduras de Serpentes/complicações , Mordeduras de Serpentes/terapia , Bothrops atrox , Brasil , Acidente Vascular Cerebral Hemorrágico/complicações , Hospitais , Antivenenos
5.
Pharmaceutics ; 16(3)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38543226

RESUMO

The landscape of medical treatments is undergoing a transformative shift. Precision medicine has ushered in a revolutionary era in healthcare by individualizing diagnostics and treatments according to each patient's uniquely evolving health status. This groundbreaking method of tailoring disease prevention and treatment considers individual variations in genes, environments, and lifestyles. The goal of precision medicine is to target the "five rights": the right patient, the right drug, the right time, the right dose, and the right route. In this pursuit, in silico techniques have emerged as an anchor, driving precision medicine forward and making this a realistic and promising avenue for personalized therapies. With the advancements in high-throughput DNA sequencing technologies, genomic data, including genetic variants and their interactions with each other and the environment, can be incorporated into clinical decision-making. Pharmacometrics, gathering pharmacokinetic (PK) and pharmacodynamic (PD) data, and mathematical models further contribute to drug optimization, drug behavior prediction, and drug-drug interaction identification. Digital health, wearables, and computational tools offer continuous monitoring and real-time data collection, enabling treatment adjustments. Furthermore, the incorporation of extensive datasets in computational tools, such as electronic health records (EHRs) and omics data, is also another pathway to acquire meaningful information in this field. Although they are fairly new, machine learning (ML) algorithms and artificial intelligence (AI) techniques are also resources researchers use to analyze big data and develop predictive models. This review explores the interplay of these multiple in silico approaches in advancing precision medicine and fostering individual healthcare. Despite intrinsic challenges, such as ethical considerations, data protection, and the need for more comprehensive research, this marks a new era of patient-centered healthcare. Innovative in silico techniques hold the potential to reshape the future of medicine for generations to come.

6.
J Mycol Med ; 34(1): 101464, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38367460

RESUMO

INTRODUCTION: The cases of dermatophytosis are increasing and they are associated with a higher number of therapeutic failures leading the doctor to prescribe combinations of antifungals as therapy. The objective was to evaluate the interaction of terbinafine and ciclopirox, the most commonly antifungals used in the clinic, in dermatophyte isolates. METHODOLOGY: The minimum inhibitory concentrations (MIC) of ciclopirox and terbinafine were determined by the broth microdilution method according CLSI and the checkerboard assay was used to evaluate the interaction between the antifungal agents. RESULTS: For terbinafine the mic50 was 0.125 ug/mL and mic90 was 0.250 ug/mL. For ciclopirox the values were 2.0 ug/mL for mic50 and 4.0 ug/mL for mic90. No synergistic interaction was observed for the dermatophyte isolates tested. CONCLUSION: These results suggest that the use of terbinafine in combination with ciclopirox, which is widely used in the clinic, may not be a good choice for the treatment of onychomycosis.


Assuntos
Antifúngicos , Onicomicose , Humanos , Terbinafina/farmacologia , Terbinafina/uso terapêutico , Ciclopirox/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Onicomicose/tratamento farmacológico , Onicomicose/microbiologia , Testes de Sensibilidade Microbiana
7.
Nat Commun ; 15(1): 1822, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418445

RESUMO

Protection from direct human impacts can safeguard marine life, yet ocean warming crosses marine protected area boundaries. Here, we test whether protection offers resilience to marine heatwaves from local to network scales. We examine 71,269 timeseries of population abundances for 2269 reef fish species surveyed in 357 protected versus 747 open sites worldwide. We quantify the stability of reef fish abundance from populations to metacommunities, considering responses of species and functional diversity including thermal affinity of different trophic groups. Overall, protection mitigates adverse effects of marine heatwaves on fish abundance, community stability, asynchronous fluctuations and functional richness. We find that local stability is positively related to distance from centers of high human density only in protected areas. We provide evidence that networks of protected areas have persistent reef fish communities in warming oceans by maintaining large populations and promoting stability at different levels of biological organization.


Assuntos
Conservação dos Recursos Naturais , Peixes , Animais , Humanos , Peixes/fisiologia , Oceanos e Mares , Clima , Ecossistema , Recifes de Corais
8.
Cell Death Discov ; 10(1): 24, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216593

RESUMO

Modeling human neuronal properties in physiological and pathological conditions is essential to identify novel potential drugs and to explore pathological mechanisms of neurological diseases. For this purpose, we generated a three-dimensional (3D) neuronal culture, by employing the readily available human neuroblastoma SH-SY5Y cell line, and a new differentiation protocol. The entire differentiation process occurred in a matrix and lasted 47 days, with 7 days of pre-differentiation phase and 40 days of differentiation, and allowed the development of a 3D culture in conditions consistent with the physiological environment. Neurons in the culture were electrically active, were able to establish functional networks, and showed features of cholinergic neurons. Hence here we provide an easily accessible, reproducible, and suitable culture method that might empower studies on synaptic function, vesicle trafficking, and metabolism, which sustain neuronal activity and cerebral circuits. Moreover, this novel differentiation protocol could represent a promising cellular tool to study physiological cellular processes, such as migration, differentiation, maturation, and to develop novel therapeutic approaches.

9.
J Med Chem ; 67(1): 17-37, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38113353

RESUMO

Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.


Assuntos
Cardiopatias , Receptores de GABA , Humanos , Receptores de GABA/metabolismo , Membranas Mitocondriais/metabolismo , Cardiopatias/tratamento farmacológico , Cardiopatias/metabolismo , Ligantes
10.
Molecules ; 28(23)2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-38067467

RESUMO

Cancer is one of the leading causes of death worldwide. Conventional treatments such as surgery, chemotherapy, and radiotherapy have limitations and severe side effects. Magnetic hyperthermia (MH) is an alternative method that can be used alone or in conjunction with chemotherapy or radiotherapy to treat cancer. Cobalt ferrite particles were synthesized using an innovative biogenic sol-gel method with powder of coconut water (PCW). The obtained powders were subjected to heat treatments between 500 °C and 1100 °C. Subsequently, they were characterized by thermal, structural, magnetic, and cytotoxic analyses to assess their suitability for MH applications. Through X-ray diffraction and Raman spectroscopy, it was possible to confirm the presence of the pure phase of CoFe2O4 in the sample treated at 1100 °C, exhibiting a saturation magnetization of 84 emu/g at 300 K and an average grain size of 542 nm. Furthermore, the sample treated at 1100 °C showed a specific absorption rate (SAR) of 3.91 W/g, and at concentrations equal to or below 5 mg/mL, is non-cytotoxic, being the most suitable for biomedical applications.


Assuntos
Magnetismo , Neoplasias , Humanos , Cobalto/química , Compostos Férricos/química
11.
J Funct Biomater ; 14(12)2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38132819

RESUMO

This study explores the effectiveness of the antineoplastic agent 5-FU in cancer cells by leveraging the unique properties of cationic antimicrobial peptides (CAMPs) and cell-penetrating peptides (CPPs). Traditional anticancer therapies face substantial limitations, including unfavorable pharmacokinetic profiles and inadequate specificity for tumor sites. These drawbacks often necessitate higher therapeutic agent doses, leading to severe toxicity in normal cells and adverse side effects. Peptides have emerged as promising carriers for targeted drug delivery, with their ability to selectively deliver therapeutics to cells expressing specific receptors. This enhances intracellular drug delivery, minimizes drug resistance, and reduces toxicity. In this research, we comprehensively evaluate the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of various AMPs and CPPs to gain insights into their potential as anticancer agents. The peptide synthesis involved a solid-phase synthesis using a Liberty Microwave Peptide Synthesizer. The peptide purity was confirmed via LC-MS and HPLC methods. For the ADMET screening, computational tools were employed, assessing parameters like absorption, distribution, metabolism, excretion, and toxicity. The cell lines A549 and UM-UC-5 were cultured and treated with 5-FU, CAMPs, and CPPs. The cell viability was measured using the MTT assay. The physicochemical properties analysis revealed favorable drug-likeness attributes. The peptides exhibited potential inhibitory activity against CYP3A4. The ADMET predictions indicated variable absorption and distribution characteristics. Furthermore, we assessed the effectiveness of these peptides alone and in combination with 5-FU, a widely used antineoplastic agent, in two distinct cancer cell lines, UM-UC-5 and A549. Our findings indicate that CAMPs can significantly reduce the cell viability in A549 cells, while CPPs exhibit promising results in UM-UC-5 cells. Understanding these multifaceted effects could open new avenues for antiviral and anticancer research. Further, experimental validation is necessary to confirm the mechanism of action of these peptides, especially in combination with 5-FU.

12.
Animals (Basel) ; 13(24)2023 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-38136914

RESUMO

After parturition, a rapid transition occurs from the intrauterine to the extrauterine milieu, exposing neonates to physiological circumstances characterized by oxidative conditions that instigate the generation of reactive oxygen species. These free radicals play pivotal roles in physiological processes; however, an imbalance between their production and the removal of antioxidants can result in severe cellular damage. The main objective of this study was to compare the oxidative and antioxidant profiles in mule and horse neonates immediately post-parturition, as well as at subsequent time points (1, 6, 12, and 24 h, 7 and 30 days) during their extrauterine existence. The parameters assessed included the systemic concentrations of Thiobarbituric Acid Reactive Substances (TBARS) and carbonyl groups; the activities of the antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx); and the levels of the total, indirect, and direct bilirubin. Our results showed no interaction effect between the neonatal groups and the assessed time points for the variables under investigation. Notably, the concentrations of TBARS, as a marker of lipid peroxidation, and bilirubin were consistently lower in the mules, whereas the glutathione peroxidase (GPx) activity exhibited higher levels in this group. The bilirubin levels were notably reduced in the mule neonates. The TBARS demonstrated a progressive decrease over the observation period in both groups, while the GPx activity remained relatively stable from birth to 7 days, with a substantial increase evident at the 30-day mark. Protein oxidation was not affected by the group and time, while for the SOD values, all times were statistically similar, except for the lower activity at T1h. Consequently, our findings lead us to the conclusion that neonatal mules and horses manifest distinct patterns of oxidative activity and antioxidant capacity during the initial month of their extrauterine existence, potentially indicative of different adaptation mechanisms to the extrauterine environment.

13.
Sci Rep ; 13(1): 17671, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37848614

RESUMO

Aging is the basis for several unfavorable conditions, including cardiovascular diseases (CVDs). In this sense, regular physical activity (regular PA) has been proven to delay cellular aging and prevent endothelial dysfunction related to CVDs. Despite numerous studies involving athletes, little is known about cellular and molecular mechanisms of regular PA among master athletes. The present study aimed at evaluating the effects of regular PA on local microcirculatory functions in elderly athletes as compared to age-matched sedentary controls. Moreover, molecular/epigenetic mechanisms (nitric oxide, oxidative stress, PGC-1α, SIRT1 and miR29) were also assessed. The results of the present study showed that regular PA significantly increased local blood flow in post-ischemia and post-heating conditions, as well as NO plasma concentrations, denoting a better endothelial function/microcirculatory efficiency. Moreover, athletes presented a greater plasma antioxidant and increased transcriptional levels of the metabolism regulator PGC-1α. Finally, regular PA enhanced plasma level of SIRT1 and miR29, suggested as epigenetic regulators of redox balance and cellular metabolism. In addition, stimulated local blood flow was directly related to plasma antioxidant capacity, and SIRT1 and miR29 levels. Overall, our data confirm the beneficial effects of regular PA on the cardiovascular profile in elderly athletes and shed light on molecular signals involved in the positive adaptations to exercise.


Assuntos
Doenças Cardiovasculares , Doenças Vasculares , Humanos , Idoso , Antioxidantes/metabolismo , Sirtuína 1/genética , Microcirculação , Exercício Físico/fisiologia , Envelhecimento , Óxido Nítrico
14.
AAPS PharmSciTech ; 24(7): 198, 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37783861

RESUMO

Terbinafine hydrochloride is a synthetic allylamine whose mechanism of action consists of inhibiting the enzyme squalene epoxidase that participates in the first stage of ergosterol synthesis, interfering with fungal membrane function. Ozonated oils are used for topical application of ozone, producing reactive oxygen species that cause cellular damage in microorganisms, therefore being an alternative treatment for acute and chronic skin infections. This study aimed to develop and characterize Eudragit® RS100 nanocapsules, obtained by interfacial deposition of preformed polymer method, containing 0.5% terbinafine hydrochloride and 5% ozonated sunflower seed oil as a potential treatment against dermatophytes. The polymeric nanocapsules were characterized regarding particle size, zeta potential, pH, drug content, encapsulation efficiency, and stability. The in vitro drug release, in vitro skin permeation, and in vitro antifungal activity were also evaluated. The particle size was around 150 nm with a narrow size distribution, the zeta potential was around + 6 mV, and the pH was 2.2. The drug content was close to 95% with an encapsulation efficiency of 53%. The nanocapsules were capable to control the drug release and the skin permeation. The in vitro susceptibility test showed greater antifungal activity for the developed nanocapsules, against all dermatophyte strains tested, compared to the drug solution. Therefore, the polymeric nanocapsules suspension containing terbinafine hydrochloride and ozonated oil can be considered a potential high-efficacy candidate for the treatment of dermatophytosis, with a possible reduction in the drug dose and frequency of applications. Studies to evaluate safety and efficacy in vivo still need to be performed.


Assuntos
Arthrodermataceae , Nanocápsulas , Terbinafina , Antifúngicos , Nanocápsulas/química , Óleos
15.
Int J Mol Sci ; 24(19)2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37834078

RESUMO

This review investigates the intricate role of human endogenous retroviruses (HERVs) in cancer development and progression, explicitly focusing on HERV-K (HML-2). This paper sheds light on the latest research advancements and potential treatment strategies by examining the historical context of HERVs and their involvement in critical biological processes such as embryonic development, immune response, and disease progression. This review covers computational modeling for drug-target binding assessment, systems biology modeling for simulating HERV-K viral cargo dynamics, and using antiviral drugs to combat HERV-induced diseases. The findings presented in this review contribute to our understanding of HERV-mediated disease mechanisms and provide insights into future therapeutic approaches. They emphasize why HERV-K holds significant promise as a biomarker and a target.


Assuntos
Retrovirus Endógenos , Neoplasias , Infecções Tumorais por Vírus , Humanos , Neoplasias/virologia , Infecções Tumorais por Vírus/virologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-37792211

RESUMO

This study formulated sweet potato chips with powdered potentially probiotic Levilactobacillus brevis (SPLB) and Lactiplantibacillus plantarum (SPLP) and evaluated their impacts on human intestinal microbiota during 48 h of in vitro colonic fermentation. L. brevis and L. plantarum kept high viable cell counts (> 6 log CFU/g) on sweet potato chips after freeze-drying and during 60 days of storage. SPLB and SPLP had satisfactory quality parameters during 60 days of storage. SPLB and SPLP increased the relative abundance of Lactobacillus ssp./Enterococcus spp. (3.84-10.22%) and Bifidobacterium spp. (3.25-12.45%) and decreased the relative abundance of Bacteroides spp./Prevotella spp. (8.56-2.16%), Clostridium histolyticum (8.23-2.33%), and Eubacterium rectale/Clostridium coccoides (8.07-1.33%) during 48 h of in vitro colonic fermentation. SPLB and SPLP achieved high positive prebiotic indexes (> 8.24), decreased pH values and sugar contents, and increased lactic acid and short-chain fatty acid production, proving selective stimulatory effects on beneficial bacterial groups forming the intestinal microbiota. The results showed that SPLB and SPLP have good stability and high viable cell counts of L. brevis and L. plantarum when stored under room temperature and caused positive impacts on human intestinal microbiota, making them potentially probiotic non-dairy snack options.

17.
Cureus ; 15(9): e45705, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37876397

RESUMO

Since it was described, wide-awake local anaesthesia no tourniquet (WALANT) has gained popularity. Our department has started using WALANT for hand surgery with increasing complexity. We present our results with WALANT rhizarthrosis surgery, including prosthetic replacement, trapeziectomy with suture button suspensionplasty and revision surgery. A retrospective review of all rhizarthrosis procedures under WALANT was performed from April 2021 to July 2022. We included patients who fulfilled inclusion criteria and had adequate imaging and clinical follow-up. A satisfaction survey was performed by telephone. Surgical time, complications, conversion to conventional anesthesia, pain, anxiety and global satisfaction were recorded. Tumescent anesthesia is performed 20-25 minutes before surgery, and is performed in four or five strategic locations that allow adequate anesthesia and vasoconstriction for the procedure to be comfortably carried out. We observed a series of 16 sequential surgeries involving 14 patients. All were female with a mean age of 65 years. Fourteen cases were performed due to primary rhizarthrosis, eight trapeziectomies with suture button suspensionplasty, six prosthetic replacements, and two revision surgeries. One patient needed to be converted to conventional anaesthesia due to anxiety during the procedure. Mean procedure time was 73 minutes. There were no WALANT-related complications. Mean patient-reported satisfaction with the anesthetic technique was a 9 (on a scale from 1 to 10) and 100% of patients would choose to undergo surgery with WALANT anesthesia for a future procedure. We find it useful to actively engage the patients during surgery to keep them comfortable and also help the surgeons assess stability and functional results. After wound closure, the hand is shown to the patient and he performs various tasks. There is somewhat of a learning curve for rhizarthrosis surgery under WALANT; patient comfort can be achieved through an adequate anesthetic technique and reassurance before and during surgery. We recommend that the first few cases be done in the presence of an anesthesiologist and a fasting patient in case there is a need to convert to conventional anesthesia. Wide awake rhizarthrosis surgery, even revision surgery, is safe and pain-free. Patient-reported satisfaction is also high. The authors find that including patient participation in their own surgery might be promising for post-op rehabilitation. There are limitations in this study such as the absence of a control conventional anesthesia group, the satisfaction questionnaire was not done immediately post-operatively, as such, a memory bias cannot be excluded, and it is not yet validated for the Portuguese population.

18.
Dev Cell ; 58(19): 1967-1982.e8, 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-37734383

RESUMO

Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.


Assuntos
Neuroblastoma , Piperazinas , Piridinas , Tretinoína , Animais , Camundongos , Humanos , Linhagem Celular Tumoral , Diferenciação Celular , Tretinoína/farmacologia , Neuroblastoma/tratamento farmacológico , Adrenérgicos/uso terapêutico
19.
Mol Neurobiol ; 60(12): 7080-7087, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37526895

RESUMO

Intellectual disability (ID) is a condition characterized by significant limitations in both cognitive development and adaptive behavior. The diagnosis is made through clinical assessment, standardized tests, and intelligence quotient (IQ). Genetic, inflammation, oxidative stress, and diet have been suggested to contribute to ID, and biomarkers could potentially aid in diagnosis and treatment. Study included children and adolescents aged 6-16 years. The ID group (n = 16) and the control group (n = 18) underwent the Wechsler Intelligence Scale for Children (WISC-IV) test, and blood samples were collected. Correlations between biomarker levels and WISC-IV test scores were analyzed. The ID group had an IQ score below 75, and the values of four domains (IQ, IOP, IMO, and IVP) were lower compared to the control group. Serum levels of FKN, NGF-ß, and vitamin B12 were decreased in the ID group, while DCFH and nitrite levels were increased. Positive correlations were found between FKN and the QIT and IOP domains, NGF and the QIT and IMO domains, and vitamin B12 and the ICV domain. TNF-α showed a negative correlation with the ICV domain. Our study identified FKN, NGF-ß, and vitamin B12 as potential biomarkers specific to ID, which could aid in the diagnosis and treatment of ID. TNF-α and oxidative stress biomarkers suggest that ID has a complex etiology, and further research is needed to better understand this condition and develop effective treatments. Future studies could explore the potential implications of these biomarkers and develop targeted interventions based on their findings.


Assuntos
Deficiência Intelectual , Fator de Necrose Tumoral alfa , Humanos , Criança , Adolescente , Biomarcadores , Cognição , Vitamina B 12
20.
J Mycol Med ; 33(3): 101411, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37413753

RESUMO

The increasing resistance to antifungal agents associated with toxicity and interactions turns therapeutic management of fungal infections difficult. This scenario emphasizes the importance of drug repositioning, such as nitroxoline - a urinary antibacterial agent that has shown potential antifungal activity. The aims of this study were to discover the possible therapeutic targets of nitroxoline using an in silico approach, and to determine the in vitro antifungal activity of the drug against the fungal cell wall and cytoplasmic membrane. We explored the biological activity of nitroxoline using PASS, SwissTargetPrediction and Cortellis Drug Discovery Intelligence web tools. After confirmation, the molecule was designed and optimized in HyperChem software. GOLD 2020.1 software was used to predict the interactions between the drug and the target proteins. In vitro investigation evaluated the effect of nitroxoline on the fungal cell wall through sorbitol protection assay. Ergosterol binding assay was carried out to assess the effect of the drug on the cytoplasmic membrane. In silico investigation revealed biological activity with alkane 1-monooxygenase and methionine aminopeptidase enzymes, showing nine and five interactions in the molecular docking, respectively. In vitro results exhibited no effect on the fungal cell wall or cytoplasmic membrane. Finally, nitroxoline has potential as an antifungal agent due to the interaction with alkane 1-monooxygenase and methionine aminopeptidase enzymes, which are not the main human therapeutic targets. These results have potentially revealed a new biological target for the treatment of fungal infections. We also consider that further studies are required to confirm the biological activity of nitroxoline on fungal cells, mainly the confirmation of the alkB gene.


Assuntos
Aminopeptidases , Antifúngicos , Humanos , Antifúngicos/farmacologia , Simulação de Acoplamento Molecular , Citocromo P-450 CYP4A , Metionina , Fungos
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