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1.
J Am Chem Soc ; 144(38): 17651-17660, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36121306

RESUMO

Hydrogen sulfide (H2S) is an endogenously produced gaseous signaling molecule with important roles in regulating organelle function and stress. Because of its high reactivity, targeted delivery of H2S using small molecule H2S donors has garnered significant interest to minimize off-target effects. Although mitochondrially targeted H2S donors, such as AP39, have been reported previously and exhibit significantly higher potency than nontargeted donors, the expansion of targeted H2S delivery to other subcellular organelles remains largely absent. To fill this key unmet need, we report a library of organelle-targeted H2S donors that localize H2S delivery to specific subcellular organelles, including the Golgi apparatus, lysosome, endoplasmic reticulum, and mitochondria. We measured H2S production in vitro from each donor, confirmed the localization of H2S delivery using organelle-specific H2S responsive fluorescent probes, and demonstrated enhanced potency of these targeted H2S donors in providing protection against organelle-specific stress. We anticipate this class of targeted H2S donors will enable future studies of subcellular roles of H2S and the pathways by which H2S alleviates subcellular organelle stress.


Assuntos
Sulfeto de Hidrogênio , Corantes Fluorescentes/metabolismo , Sulfeto de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Organelas/metabolismo , Transdução de Sinais
2.
Free Radic Biol Med ; 190: 148-157, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35940516

RESUMO

Reactive oxygen species (ROS) are important modulators of physiological signaling and play important roles in bone tissue regulation. Both reactive sulfur species (RSS) and reactive selenium species (RSeS) are involved in ROS signaling, and recent work suggests RSS and RSeS involvement in the regulation of bone homeostasis. For example, RSS can promote osteogenic differentiation and decrease osteoclast activity and differentiation, and the antioxidant activity of RSeS play crucial roles in balancing bone remodeling. Here, we outline current research progress on the application of RSS and RSeS in bone disease and regeneration. Focusing on these investigations, we highlight different methods, tools, and sources of RSS and RSeS, and we also highlight future opportunities for delivery of RSS and RSeS in biological environments relating to bone.


Assuntos
Selênio , Osso e Ossos , Homeostase , Osteogênese , Espécies Reativas de Oxigênio , Enxofre
3.
Chem Asian J ; 17(16): e202200426, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35696559

RESUMO

Hydrogen sulfide is a biologically important molecule and developing chemical tools that enable further investigations into the functions of H2 S is essential. Fluorescent turn-on H2 S probes have been developed for use in cellulo and in vivo, but the membrane permeability of these probes can lead to probe leakage and signal attenuation over time. Here we report a cell trappable fluorescent probe for H2 S, CT-MeRhoAz, which is based on a methylrhodolazide scaffold derivatized with an acetoxymethyl ester group. Prior to ester cleavage, the CT-MeRhoAz probe generates a 2500-fold turn-on response to H2 S, which is enhanced to a 3000-fold response for the carboxylic acid form of the probe. Additionally, the probe is highly selective for H2 S over other biologically relevant sulfur, oxygen, and nitrogen-based analytes. Live cell imaging experiments confirmed the biocompatibility of CT-MeRhoAz and also that it is cell trappable, unlike the parent MeRhoAz scaffold.


Assuntos
Sulfeto de Hidrogênio , Xantonas , Ésteres , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/metabolismo
4.
J Org Chem ; 84(22): 14469-14475, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31479268

RESUMO

Hydrogen sulfide (H2S) is a biologically relevant molecule, and recent efforts have focused on developing small molecular donors that deliver H2S on demand. Acid-activated donors have garnered significant interest due to the potential application of such systems in myocardial ischemia injury or for suppressing tumor growth. In this work, we report a new strategy for tuning H2S delivery to a specific pH window. Specifically, we utilize self-immolative thiocarbamates with an imine-derived triggering group. After imine hydrolysis, the self-immolative decomposition releases carbonyl sulfide (COS), which is quickly hydrolyzed to H2S by carbonic anhydrase. Although acid-mediated hydrolysis results in imine cleavage, environments that are too acidic result in protonation of the aniline intermediate and results in inhibition of COS/H2S release. Taken together, this mechanism enables access to donor motifs that are only activated within specific pH windows. Here, we demonstrate the design, preparation, and pH evaluation of a series of imine-based COS/H2S donor motifs, which we anticipate that will have utility in investigating H2S in acidic microenvironments.


Assuntos
Sulfeto de Hidrogênio/química , Óxidos de Enxofre/química , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estrutura Molecular
5.
Free Radic Biol Med ; 131: 393-398, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579781

RESUMO

Investigations into hydrogen sulfide (H2S) signaling pathways have demonstrated both the generation and importance of persulfides, which are reactive sulfur species that contain both reduced and oxidized sulfur. These observations have led researchers to suggest that oxidized sulfur species, including sulfane sulfur (S0), are responsible for many of the physiological phenomena initially attributed to H2S. A common method of introducing S0 to biological systems is the administration of organic polysulfides, such as diallyl trisulfide (DATS). However, prior reports have demonstrated that commercially-available DATS often contains a mixture of polysulfides, and furthermore a lack of structure-activity relationships for organic polysulfides has limited our overall understanding of different polysulfides and their function in biological systems. Advancing our interests in the chemical biology of reactive sulfur species including H2S and S0, we report here our investigations into the rates and quantities of H2S release from a series of synthetic, pure benzyl polysulfides, ranging from monosulfide to tetrasulfide. We demonstrate that H2S is only released from the trisulfide and tetrasulfide, and that this release requires thiol-mediated reduction in the presence of cysteine or reduced glutathione. Additionally, we demonstrate the different effects of trisulfides and tetrasulfides on cell proliferation in murine epithelial bEnd.3 cells.


Assuntos
Compostos Alílicos/química , Células Endoteliais/efeitos dos fármacos , Sulfeto de Hidrogênio/química , Sulfetos/química , Sulfetos/síntese química , Compostos Alílicos/farmacologia , Animais , Encéfalo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína/química , Cisteína/farmacologia , Células Endoteliais/citologia , Glutationa/química , Glutationa/farmacologia , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Camundongos , Oxirredução , Sulfetos/farmacologia
6.
Chemistry ; 23(17): 4051-4054, 2017 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-28198117

RESUMO

Selective tuning of arylethynyl urea scaffolds for anionic guests requires an understanding of preferred binding motifs of the host-guest interaction. To investigate the binding preference of receptors without a pre-organized binding pocket, two electron-deficient phenylacetylene receptors with a single urea moiety have been prepared and were found to bind halides as 2:1 host-guest complexes that feature key CH-anion or anion-π interactions. These supporting interactions also appear to influence the mechanism of the 2:1 binding event.


Assuntos
Alcinos/química , Ânions/química , Ureia/análogos & derivados , Ureia/química , Alcinos/síntese química , Elétrons , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Estrutura Molecular , Ureia/síntese química
7.
Prim Health Care Res Dev ; 16(4): 415-23, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25370433

RESUMO

AIM: To establish how people with psoriasis in the United Kingdom today experience living with their condition including diagnosis, treatment, healthcare provision and impact on daily life. BACKGROUND: Psoriasis is a debilitating long-term inflammatory skin disease which can result in severe itching, discomfort and soreness, and may be associated with problems beyond the specific symptoms related to the skin. For many it is accompanied by difficult-to-manage treatment regimes, emotional distress and a negative impact on their quality of life and psychosocial functioning. To date there is little published information about the health experiences of people in the United Kingdom with psoriasis. METHODS: A postal self-administered questionnaire was completed by members of the Psoriasis Association and the responses analysed (n = 1564). FINDINGS: The findings suggest some similarities to surveys in other nations, but specifically highlighted that patients feel under-informed and are dissatisfied with current treatment regimes. Responses provided an insight into aspects of the condition that treatments should be targeting. Specific areas of negative impact on psychosocial functioning were identified, including the lack of available support for those experiencing emotional distress. The research provides important information about how the care of patients with psoriasis can be improved, especially at primary care level. This includes: improved training in psoriasis knowledge and awareness at general practitioner level and greater use of dermatology specialist nurses in primary care settings; more effective and manageable treatment regimes that target visible areas and general well-being; greater support for emotional distress and psychosocial functioning.


Assuntos
Atitude Frente a Saúde , Atenção à Saúde , Psoríase/psicologia , Psoríase/terapia , Qualidade de Vida/psicologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Inquéritos e Questionários , Reino Unido
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