RESUMO
The lack of secure therapies for hyperpigmentation disorders, without serious adverse effects, and the latest reports relating melanogenic disorders with development of neurodegenerative diseases, encourage the continuing search for new drugs for the treatment of such disorders. In this sense, the plant kingdom is an important source of bioactive natural products with great potential for the research and development of new therapeutics. The present study evaluated the anti-melanogenic activity of the natural methoxylated chalcone, 2',6'-dihydroxy-4'-methoxy-3'-methylchalcone (Triangularin, T), on diphenolase activity from mushroom tyrosinase and on murine B16F0 melanoma cell model. In addition, molecular modelling studies were carried out in order to understand the inhibitory activity observed. T showed a potent anti-melanogenic activity being more active than kojic acid (KA) on tyrosinase isolated of both sources and on intracellular tyrosinase. Molecular docking studies displayed important interactions between T and the active site of tyrosinase. Our results suggest that T may be useful for the treatment of hyperpigmentary disorders.
Assuntos
Melanoma/tratamento farmacológico , Humanos , Simulação de Acoplamento MolecularRESUMO
Two new prenylated flavanones, pazentin A (3',4'-dihydroxy-6,2'-diprenylpinocembrin, 1) and pazentin B [4'-hydroxy-2'-methoxy-5'-(1â´, 1â´-dimethylallyl)-6-prenylpinocembrin, 2] together with two known ones (3 and 4) previously isolated from other Dalea species were obtained from the benzene extract of Dalea pazensis Rusby roots. The compounds were evaluated in vitro for their inhibition on mushroom tyrosinase enzyme and in relation to their effect on melanogenesis in B16 murine melanoma cells, by using a spectrophotometric method. The information obtained could be relevant to the knowledge of the structure-activity relationship for these flavonoids with the aim to explore the rational design for skin-whitening agents.
Assuntos
Agaricales/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fabaceae/química , Flavanonas/química , Flavanonas/farmacologia , Melaninas/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Raízes de Plantas/química , PrenilaçãoRESUMO
Head and neck squamous cell carcinoma (HNSCC) is painful, and perineural invasion (PNI) has been associated with the worst pain. Pain due to HNSCC is diverse and may vary based on clinicopathological factors. This study aims to characterize different pain patterns linked with PNI, its influence on daily functioning, and gain insights into molecular changes and pathways associated with PNI-related pain in HNSCC patients. We conducted a cross-sectional study across 3 medical centers (n = 114), assessing pain phenotypes and their impact on daily functioning using 2 self-reported pain questionnaires, given to patients prior to their cancer surgery. Furthermore, we conducted RNA-seq analysis utilizing the The Cancer Genome Atlas dataset of HNSCC tumor from patients (n = 192) to identify genes relevant to both PNI and pain. Upon adjusting for demographic and clinicopathological variables using linear regression models, we found that PNI independently predicted function-evoked pain according to the University of Calfornia San Francisco Oral Cancer Pain Questionnaire, as well as the worst pain intensity reported in the Brief Pain Inventory. Distinct pain patterns were observed to be associated with daily activities in varying manners. Our molecular analyses revealed significant disruptions in pathways associated with the extracellular matrix structure and organization. The top differentially expressed genes linked to the extracellular matrix are implicated in cancer development, pain, and neurodegenerative diseases. Our data underscore the importance of properly categorizing pain phenotypes in future studies aiming to uncover mechanistic underpinnings of pain. Additionally, we have compiled a list of genes of interest that could serve as targets for both cancer and cancer pain management. PERSPECTIVE: PNI independently predicts function-evoked pain. Different pain phenotypes affect daily activities differently. We identified a list of candidate genes involved in the extracellular matrix structure and function that can be targeted for both cancer and cancer pain control.
RESUMO
Alzheimer's disease (AD) involves a neurodegenerative process that has not yet been prevented, reversed, or stopped. Continuing with the search for natural pharmacological treatments, flavonoids are a family of compounds with proven neuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source of bioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolated from Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposing neural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices of old 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotective effect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activity in this model are a 5'-dimethylallyl and 4'-hydroxy at the B ring. In order to search the mechanistic performance of the most active flavanone, we focus on the flavonoid-mediated regulation of GSK-3ß-mediated tau phosphorylation previously reported. Flavanone 1 treatment decreased the rise of hyperphosphorylated tau protein neuronal levels induced after 3xTg-AD ACM exposure and inhibited the activity of GSK-3ß. Finally, direct exposure of these neurotoxic 3xTg-AD astrocytes to flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our results allow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development and design of future drug therapies for AD.
Assuntos
Doença de Alzheimer , Flavanonas , Fármacos Neuroprotetores , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos Transgênicos , Proteínas tau/metabolismo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Fosforilação , Peptídeos beta-Amiloides/metabolismoRESUMO
Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARγ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, acute or chronic CIPN was introduced by short or long-term treatment of oxaliplatin in BALB/c mice. CIPN mice were treated with either a novel blood-brain barrier (BBB) penetrable PPARγ agonist ELB00824, or a BBB non-penetrable PPARγ agonist pioglitazone, or vehicle. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring byproducts of protein oxidation (carbonyl and 3-Nitrotyrosine) and lipid peroxidation [Thiobarbituric acid reactive substances (TBARS)], as wells as gene expression of Cat, Sod2, Ppargc1a. The effects of ELB00824 on nociceptor excitability were measured using whole-cell electrophysiology of isolated dorsal root ganglion neurons. Preemptive ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4- neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress.
Assuntos
Antineoplásicos , Hipersensibilidade , Neuralgia , Animais , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Hipersensibilidade/tratamento farmacológico , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/prevenção & controle , Neurônios/metabolismo , Oxaliplatina , Estresse Oxidativo , PPAR gama/metabolismoRESUMO
Neurodegenerative diseases (NDs) represent a global problem on public health, with a growing incidence as human longevity increases. Currently, although there are palliative strategies available for most of these diseases, there is a lack of effective therapies for their cure. Flavonoids are extensively studied for their multi-target behavior. Among numerous biological activities, it has been reported that they act at the CNS level, presenting neuroprotective activity through different mechanisms of action. Dalea L. (Fabaceae) is an American genus, with about 172 species. Dalea elegans Gillies ex. Hook. & Arn and Dalea pazensis Rusby, both South American species, are the important source of natural compounds of the prenylated flavanones type. In the present study, five prenylated flavanones isolated from Dalea species were assayed for their neuroprotective activity in two in vitro models of neurodegeneration. Flavanones 1 and 2 exhibited neuroprotective effects against oxidative stress-induced death in both models, granular cerebellar neurons and (NGF)-differentiated PC12 cells. Structure-activity relationships were also reported. Our results indicated that an 8-prenyl group at the A-ring accompanied by an unsubstituted B-ring, or a 2',4'-dihydroxy-5'-dimethylallyl substitution, lead to the most potent flavanones. Furthermore, in silico studies were performed, and several putative targets in NDs were identified for compounds 1 and 2. Between them, the enzyme acetylcholinesterase was selected for its validation in vitro. The present in vitro and in silico results imply that prenylated flavanones 1 and 2 may be useful in the development and design of future strategies for the treatment of NDs diseases.