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iScience ; 27(2): 108968, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38327788


Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the clinic. Here we have identified that the natural product brazilin effectively inhibits both priming and activation of the NLRP3 inflammasome in cultured murine macrophages, a human iPSC microglial cell line and in a mouse model of acute peritoneal inflammation. Through computational modeling, we predict that brazilin can adopt a favorable binding pose within a site of the NLRP3 protein which is essential for its conformational activation. Our results not only encourage further evaluation of brazilin as a therapeutic agent for NLRP3-related inflammatory diseases, but also introduce this small-molecule as a promising scaffold structure for the development of derivative NLRP3 inhibitor compounds.

Cancer Metastasis Rev ; 43(1): 261-292, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38169011


Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed.

Transição Epitelial-Mesenquimal , Neoplasias , Humanos , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais , Adaptação Fisiológica , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
J Homosex ; 71(1): 166-192, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35930805


Although emerging adulthood is recognized as a pivotal time for relationship development, most studies concern heterosexual youth or older sexual minority partners. Using narratives from 40 college student emerging adults, we sought to understand the particularities and generalities of lesbian, gay, bisexual and other sexual minority (LGB+) relationship experiences. Positive experiences particular to being in a LGB+ relationship concerned partner support for coming and being out; support from family members for the relationship was rarely mentioned. Negative experiences were twice as likely to be mentioned as positive ones. They concerned how partners being at different levels of outness and problems with family support stressed the relationship. Generalities pertaining to positive relationship factors included meeting needs for support and using perspective taking to deal with conflict. Negative factors included unmet needs for companionship and intimacy and breakup anxiety about whether the relationship had a future. Our findings suggest the importance of developing strength-based LGB+ affirmative education for emerging adults to promote core relationship processes and strengthen skills to cope with stressors specific to sexual minority romantic partnerships.

Homossexualidade Feminina , Minorias Sexuais e de Gênero , Adulto , Feminino , Adolescente , Humanos , Comportamento Sexual , Bissexualidade , Heterossexualidade
Expert Opin Drug Discov ; 17(6): 559-568, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35587689


INTRODUCTION: The global health burden of stroke is significant and few therapeutic treatment options currently exist for patients. Pre-clinical research relies heavily on rodent stroke models but the limitations associated with using these systems alone has meant translation of drug compounds to the clinic has not been greatly successful to date. Zebrafish disease modeling offers a potentially complementary platform for pre-clinical compound screening to aid the drug discovery process for translational stroke research. AREAS COVERED: In this review, the authors introduce stroke and describe the issues associated with the current pre-clinical drug development pipeline and the advantages that zebrafish disease modeling can offer. Existing zebrafish models of ischemic and hemorrhagic stroke are reviewed. Examples of how zebrafish models have been utilized for drug discovery in other disease disciplines are also discussed. EXPERT OPINION: Zebrafish disease modeling holds the capacity and potential to significantly enhance the stroke drug development pipeline. However, for this system to be more widely accepted and incorporated into translational stroke research, continued improvement of the existing zebrafish stroke models, as well as focussed collaboration between zebrafish and stroke researchers, is essential.

Acidente Vascular Cerebral , Peixe-Zebra , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Acidente Vascular Cerebral/tratamento farmacológico , Pesquisa Translacional Biomédica