RESUMO
Salmonellosis is a globally extensive food-borne disease, which threatens public health and results in huge economic losses in the world annually. The rising prevalence of antibiotic resistance in Salmonella poses a significant global concern, emphasizing an imperative to identify novel therapeutic agents or methodologies to effectively combat this predicament. In this study, self-assembly hydrogen sulfide (H2S)-responsive nanoprodrugs were fabricated with poly(α-lipoic acid)-polyethylene glycol grafted rhein and geraniol (PPRG), self-assembled into core-shell nanoparticles via electrostatic, hydrophilic and hydrophobic interactions, with hydrophilic exterior and hydrophobic interior. The rhein and geraniol are released from self-assembly nanoprodrugs PPRG in response to Salmonella infection, which is known to produce hydrogen sulfide (H2S). PPRG demonstrated stronger antibacterial activity against Salmonella compared with rhein or geraniol alone in vitro and in vivo. Additionally, PPRG was also able to suppress the inflammation and modulate gut microbiota homeostasis. In conclusion, the as-prepared self-assembly nanoprodrug sheds new light on the design of natural product active ingredients and provides new ideas for exploring targeted therapies for specific Enteropathogens. Graphical illustration for construction of self-assembly nanoprodrugs PPRG and its antibacterial and anti-inflammatory activities on experimental Salmonella infection in mice.
Assuntos
Sulfeto de Hidrogênio , Infecções por Salmonella , Animais , Camundongos , Salmonella typhimurium , Sulfeto de Hidrogênio/química , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/microbiologia , Antibacterianos/farmacologiaRESUMO
Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Resposta ao Choque Térmico/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica , Animais , Antineoplásicos/química , Sítios de Ligação , Biomarcadores Tumorais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Mesilato de Imatinib/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Multimerização Proteica/efeitos dos fármacos , Análise Espectral , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Food safety issues have received much attention. Biogenic amines are considered important markers of food spoilage. Accurate detection of biogenic amines is important for food quality monitoring. Herein, we developed two coumarin-difluoroboron ß-diketonate hybrid probes, 1 and 2, for detection of amines. Both probes possess large conjugated structures and donor-acceptor-donor configuration, exhibiting solvatochromic effects due to intramolecular charge transfer mechanism. Upon reaction with amines, the boron atom in difluoroboron unit can interact with lone pair electrons of nitrogen atom, thus resulting in significant changes in absorption and fluorescence properties. These probes were successfully utilized to image amine in live cells and liver tissues. Moreover, by photographing probe-loaded food extract supernatant, we establish the relationship between color parameters and food storage time, which can easily indicate food spoilage process. This work and its findings hold promise for providing potential strategies for real-time and convenient detection of food freshness.
Assuntos
Aminas Biogênicas , Corantes Fluorescentes , Corantes Fluorescentes/química , Aminas Biogênicas/análise , Aminas Biogênicas/química , Humanos , Contaminação de Alimentos/análise , Animais , Imagem Óptica , Inocuidade dos AlimentosRESUMO
Prebiotics and postbiotics have gained attention as functional food additives due to their substantial influence on the gut microbiome and potential implications for human health on a broader scale. In addition, the number of patents for these additives has also increased, yet their functional classification has been problematic. In this study, we classified 2215 patents granted from 2001 to 2020 by functionality to enable predictions of future development directions. These patents encompassed subjects as diverse as feed supplementation, regulation of intestinal homeostasis, prevention of gastrointestinal ailments, targeted drug administration and augmentation of drug potency. The progression of patents issued during this time frame could be divided into three phases: occasional accounts prior to 2001, a period from 2001 to 2013 during which an average of 42 patents were issued annually, followed by a surge exceeding 140 patents annually after 2013. The latter increase has indicated that pre- and post-biotics have been recognized as biologically relevant. Patent mining therefore can enable forecasts of the future trajectory of these biologics and provide insights to evaluate their advancement. Moreover, this research is the first attempt to generalize and predict the directions of prebiotics and postbiotics using patent information and offers a comprehensive perspective for the potential utilization of prebiotics and postbiotics across a wide variety of fields.
Assuntos
Microbioma Gastrointestinal , Probióticos , Humanos , Prebióticos , IntestinosRESUMO
Curcumin, a natural bioactive polyphenol with diverse molecular targets, is well known for its anti-oxidation and anti-inflammatory potential. However, curcumin exhibits low solubility (<1 µg mL-1), poor tissue-targeting ability, and rapid oxidative degradation, resulting in poor bioavailability and stability for inflammatory therapy. Here, poly(diselenide-oxalate-curcumin) nanoparticle (SeOC-NP) with dual-reactive oxygen species (ROS) sensitive chemical moieties (diselenide and peroxalate ester bonds) is fabricated by a one-step synthetic strategy. The results confirmed that dual-ROS sensitive chemical moieties endowed SeOC-NP with the ability of targeted delivery of curcumin and significantly suppress oxidative degradation of curcumin for high-efficiency inflammatory therapy. In detail, the degradation amount of curcumin for SeOC is about 4-fold lower than that of free curcumin in an oxidative microenvironment. As a result, SeOC-NP significantly enhanced the antioxidant activity and anti-inflammatory efficacy of curcumin in vitro analysis by scavenging intracellular ROS and suppressing the secretion of nitric oxide and pro-inflammatory cytokines. In mouse colitis models, orally administered SeOC-NP can remarkably alleviate the symptoms of IBD and maintain the homeostasis of gut microbiota. This work provided a simple and effective strategy to fabricate ROS-responsive micellar and enhance the oxidation stability of medicine for precise therapeutic inflammation.
Assuntos
Colite , Curcumina , Nanopartículas , Espécies Reativas de Oxigênio , Curcumina/química , Curcumina/farmacologia , Animais , Colite/tratamento farmacológico , Colite/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Células RAW 264.7 , Oxirredução , Antioxidantes/química , Antioxidantes/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Camundongos Endogâmicos C57BL , MasculinoRESUMO
Targeted antibiotic delivery system would be an ideal solution for the treatment of enteropathogenic infections since it avoids the excessive usage of antibiotics clinically, which may lead to threat on public health and food safety. Salmonella spp. are Enteropathogens, but they are also robust H2S producers in the intestinal tracts of hosts. To this end, the PEGylated poly (α lipoic acid) (PEG-PALA) copolymer nanoparticles with hydrophilic exterior and hydrophobic interior were designated in this study to encapsulate the antibiotics and release them in response to H2S produced by Salmonella spp. The PEG-PALA nanoparticles demonstrated excellent stability in vitro and biocompatibility toward mammalian Caco-2 and 293 T cells. The release of ciprofloxacin from PEG-PALA nanoparticle was only 25.44 ± 0.57% and 26.98 ± 1.93% (w/w) in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) solutions without H2S stimulation. However, the release amounts of ciprofloxacin were up to 73.68 ± 1.63% (w/w) in the presence of 1 mM Na2S as H2S source. In the mouse infection model, PEG-PALA nanoparticles encapsulated with ciprofloxacin (PEG-PALA@CIP) reduced the Salmonella colonization in the heart, liver, spleen, lung, cecum, and faeces, prolonged ciprofloxacin persistence in the intestine while reducing its absorption into the blood. More importantly, these nanoparticles reduced 3.4-fold of Enterobacteriaceae levels and increased 1.5-fold of the Lactobacillaceae levels compared with the drug administered in the free form. Moreover, these nanoparticles resulted in only minimal signs of intestinal tract inflammation. The H2S-responsive antibiotic delivery systems reported in this study demonstrating a variety of advantages including protected the drug from deactivation by gastric and intestinal fluids, maintained a high concentration in the intestinal tract and maximally kept the gut microbiota homeostasis. As such, this targeted antibiotic delivery systems are for the encapsulation of antibiotics to target specific enteropathogens.
Assuntos
Nanopartículas , Ácido Tióctico , Humanos , Camundongos , Animais , Ciprofloxacina/química , Células CACO-2 , Nanopartículas/química , Salmonella , Antibacterianos/química , Polietilenoglicóis/química , Sistemas de Liberação de Medicamentos , MamíferosRESUMO
Background: The association between paroxysmal vertigo and right-to-left shunt (RLS) is rarely reported. This study investigates the prevalence and correlation of RLS in patients with different paroxysmal vertigo diseases. Methods: Patients with paroxysmal vertigo from seven hospitals in China were included in this observational study between 2017 and 2021. Migraine patients within the same period were included for comparison. Demographic data and medical history were collected; contrast transthoracic echocardiography was performed; and the clinical features, Dizziness Handicap Inventory, and incidence of RLS in each group were recorded. Results: A total of 2,751 patients were enrolled. This study's results demonstrated that the proportion of RLS in patients with benign recurrent vertigo (BRV) and vestibular migraine (VM) was significantly higher than that in patients with benign paroxysmal positional vertigo, Meniere's disease, and vestibular paroxysmia (P < 0.05). No statistical difference was shown between the frequency of RLS in patients with BRV and those with migraine and VM. A positive correlation was shown between the RLS grade and Dizziness Handicap Inventory scores of patients with VM and BRV (P < 0.01) after effectively controlleding the effect of confounding variables. Conclusions: RLS was significantly associated with BRV and VM. RLS may be involved in the pathogeneses of BRV and VM and may serve as a differential reference index for the paroxysmal vertigo. Trial Registration: CHRS, NCT04939922, registered 14 June 2021- retrospectively registered, https://register.clinicaltrials.gov.