RESUMO
Extracellular vesicles (EVs) are future promising therapeutics, but their instability in vivo after administration remains an important barrier to their further development. Many groups evaluated EV surface modification strategies to add a targeting group with the aim of controlling EV biodistribution. Conversely, fewer groups focused on their stabilization to obtain "stealth" allogenic EVs. Modulating their stabilization and biodistribution is an essential prerequisite for their development as nano-therapeutics. Here, we explored polyoxazolines with lipid anchors association to the EV membrane (POxylation as an alternative to PEGylation) to stabilize EVs in plasma and control their biodistribution, while preserving their native properties. We found that this modification maintained and seemed to potentiate the immunomodulatory properties of EVs derived from mesenchymal stem/stromal cells (MSC). Using a radiolabeling protocol to track EVs at a therapeutically relevant concentration in vivo, we demonstrated that POxylation is a promising option to stabilize EVs in plasma because it increased EV half-life by 6 fold at 6 h post-injection. Moreover, EV accumulation in tumors was higher after POxylation than after PEGylation.
Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/química , Animais , Humanos , Distribuição Tecidual , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Oxazóis/química , Camundongos , Propriedades de Superfície , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , FemininoRESUMO
Micro and nanoscale patterning of surface features and biochemical cues have emerged as tools to precisely direct neurite growth into close proximity with next generation neural prosthesis electrodes. Biophysical cues can exert greater influence on neurite pathfinding compared to the more well studied biochemical cues; yet the signaling events underlying the ability of growth cones to respond to these microfeatures remain obscure. Intracellular Ca2+ signaling plays a critical role in how a growth cone senses and grows in response to various cues (biophysical features, repulsive peptides, chemo-attractive gradients). Here, we investigate the role of inositol triphosphate (IP3) and ryanodine-sensitive receptor (RyR) signaling as sensory neurons (spiral ganglion neurons, SGNs, and dorsal root ganglion neurons, DRGNs) pathfind in response to micropatterned substrates of varied geometries. We find that IP3 and RyR signaling act in the growth cone as they navigate biophysical cues and enable proper guidance to biophysical, chemo-permissive, and chemo-repulsive micropatterns. In response to complex micropatterned geometries, RyR signaling appears to halt growth in response to both topographical features and chemo-repulsive cues. IP3 signaling appears to play a more complex role, as growth cones appear to sense the microfeatures in the presence of xestospongin C but are unable to coordinate turning in response to them. Overall, key Ca2+ signaling elements, IP3 and RyR, are found to be essential for SGNs to pathfind in response to engineered biophysical and biochemical cues. These findings inform efforts to precisely guide neurite regeneration for improved neural prosthesis function, including cochlear implants.
Assuntos
Neuritos , Canal de Liberação de Cálcio do Receptor de Rianodina , Transdução de Sinais , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Neuritos/metabolismo , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/citologia , Cones de Crescimento/metabolismo , Cones de Crescimento/efeitos dos fármacos , Sinalização do Cálcio , Ratos , Propriedades de Superfície , Células Cultivadas , Oxazóis , Compostos MacrocíclicosRESUMO
Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1-15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 µM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver-Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition.
Assuntos
Melaninas , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Preparações Clareadoras de Pele , Animais , Humanos , Camundongos , Agaricales/enzimologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Melaninas/biossíntese , Melaninas/antagonistas & inibidores , Estrutura Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Pironas , Resorcinóis/química , Resorcinóis/farmacologia , Preparações Clareadoras de Pele/farmacologia , Preparações Clareadoras de Pele/química , Relação Estrutura-Atividade , Peixe-ZebraRESUMO
As a continuation of our efforts to develop new agrochemicals with typical architecture and efficient bioactivity from plant natural products, natural neolignan honokiol was used as a lead compound to prepare novel analogs bearing the core 2-aminobenzoxazole scaffold. Their insecticidal potency against two representative agricultural pests, Plutella xylostella Linnaeus and Mythimna separata (Walker), were evaluated in vivo. The pesticide bioassay results revealed that compounds 7â³a, 9, 10d, and 10j exhibited prominent larvicidal activity against the larvae of P. xylostella (LC50 = 7.95, 11.85, 15.51, and 12.06 µg/mL, respectively), superior to the precursor honokiol (LC50 = 43.35 µg/mL) and two botanical insecticides, toosendanin (LC50 = 26.20 µg/mL) and rotenone (LC50 = 23.65 µg/mL). Compounds 7d, 10d, and 10j displayed a more pronounced nonchoice antifeedant effect (AFC50 = 9.48, 9.14, and 12.41 µg/mL, respectively) than honokiol (AFC50 = 54.81 µg/mL) on P. xylostella. Moreover, compounds 7b, 7â³a, 9, 10d, 10f, and 10j showed better growth inhibitory activity against M. separata (LC50 = 0.36, 0.34, 0.28, 0.16, 0.26, and 0.11 mg/mL, respectively) than honokiol, toosendanin, and rotenone (LC50 = 1.48, 0.53, and 0.46 mg/mL, respectively). A potted plant assay under greenhouse conditions illustrated that compounds 10d and 10j continued to provide good control efficacy against P. xylostella and an apparent protective effect on plants. Further cytotoxicity assay revealed that the aforementioned potent compounds showed relatively moderate toxicity and a good safety profile for non-target mammalian cells. Overall, the current work provides valuable insight into the agrochemical innovation of honokiol-derived analogs for use as natural-inspired pesticides in agricultural pest management.
Assuntos
Compostos de Bifenilo , Inseticidas , Larva , Lignanas , Mariposas , Animais , Lignanas/farmacologia , Lignanas/química , Inseticidas/química , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Compostos de Bifenilo/química , Relação Estrutura-Atividade , Benzoxazóis/química , Benzoxazóis/farmacologia , Estrutura Molecular , Compostos Alílicos , Aminas , Oxazóis , FenóisRESUMO
Isoxazoline insecticides have shown broad-spectrum insecticidal activity against a variety of insect pests. However, the high toxicity of isoxazoline compounds towards honeybees restricts their application in crop protection. To mitigate this issue, a series of isoxazoline derivatives containing 2-phenyloxazoline were designed and synthesized. Bioassays revealed that several compounds exhibited promising insecticidal activities against Plutella xylostella, with G28 showing particularly excellent insecticidal activity, reflected by an LC50 value of 0.675 mg/L, which is comparable to that of fluxametamide (LC50 = 0.593 mg/L). Furthermore, G28 also exhibited effective insecticidal activity against Solenopsis invicta. Importantly, bee toxicity experiments indicated that G28 had significantly lower acute oral toxicity (LD50 = 2.866 µg/adult) compared to fluxametamide (LD50 = 1.083 µg/adult) and fluralaner (LD50 = 0.022 µg/adult), positioning it as a promising candidate with reduced toxicity to bees. Theoretical simulation further elucidated the reasons for the selective differences in the ability of isoxazoline to achieve higher insecticidal activity while maintaining lower bee toxicity. This research suggests that isoxazoline compounds containing 2-phenyloxazoline group hold potential as new insecticide candidates and offers insights into the development of novel isoxazoline insecticides with both high efficacy and environmental safety.
Assuntos
Desenho de Fármacos , Inseticidas , Isoxazóis , Mariposas , Oxazóis , Inseticidas/síntese química , Inseticidas/química , Inseticidas/farmacologia , Inseticidas/toxicidade , Animais , Oxazóis/química , Oxazóis/toxicidade , Isoxazóis/farmacologia , Isoxazóis/química , Mariposas/efeitos dos fármacos , Abelhas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
An evaluation was made of the larvicidal efficacy of lotilaner (Credeli®) in the treatment of dogs naturally infested with Dermatobia hominis larvae. A total of 12 dogs presenting at least three live D. hominis larvae were medicated. The animals were medicated orally with a single dose of no less than 20 mg/kg lotilaner. After drug administration, the animals remained at their homes, and observations were made to verify the larvicidal effect 6 hours after treatment. Live larvae were considered any parasite that exhibited motility after removal. For each animal was using the formula: 100 x [(total of live larvae before treatment - total live larvae after treatment) /total of live larvae before treatment] as criteria for evaluating lotilaner efficacy. A total of 98 larvae were counted in 12 dogs, with an average of 8.1 larvae per animal. The effectiveness of lotilaner was 80.6%. Nineteen larvae were found alive, albeit presenting hypomobility and lethargic behavior. However, note that the evaluation was performed just six hours after administration of the drug. Lotilaner administered orally in a single dose of 20 mg/kg showed 80.6% efficacy six hours after treating dogs naturally infested with D. hominis.
Assuntos
Dípteros , Doenças do Cão , Miíase , Animais , Cães , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Miíase/veterinária , Miíase/tratamento farmacológico , Miíase/diagnóstico , Miíase/parasitologia , Dípteros/efeitos dos fármacos , Larva/efeitos dos fármacos , Resultado do Tratamento , Masculino , Feminino , Inseticidas/administração & dosagem , Oxazóis , TiofenosRESUMO
The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP3 (inositol 1,4,5 trisphosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP3 receptor (IP3-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP3 on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts. Immunohistochemistry and confocal imaging demonstrated the presence of IP3-R2 in isolated AVN cells, with partial overlap with RyR2 ryanodine receptors seen in co-labelling experiments. In whole-cell recordings at physiological temperature, application of 10 µM membrane-permeant Bt3-(1,4,5)IP3-AM accelerated spontaneous AP rate and increased diastolic depolarization rate, without direct effects on ICa,L, IKr, If or INCX. By contrast, application via the patch pipette of 5 µM of the IP3-R inhibitor xestospongin C led to a slowing in spontaneous AP rate and prevented 10 µM Bt3-(1,4,5)IP3-AM application from increasing the AP rate. UV excitation of AVN cells loaded with caged-IP3 led to an acceleration in AP rate, the magnitude of which increased with the extent of UV excitation. 2-APB slowed spontaneous AP rate, consistent with a role for constitutive IP3-R activity; however, it was also found to inhibit ICa,L and IKr, confounding its use for studying IP3-R. Under AP voltage clamp, UV excitation of AVN cells loaded with caged IP3 activated an inward current during diastolic depolarization. Collectively, these results demonstrate that IP3 can modulate AVN cell pacemaking rate.
Assuntos
Potenciais de Ação , Nó Atrioventricular , Receptores de Inositol 1,4,5-Trifosfato , Inositol 1,4,5-Trifosfato , Miócitos Cardíacos , Animais , Coelhos , Potenciais de Ação/efeitos dos fármacos , Nó Atrioventricular/efeitos dos fármacos , Nó Atrioventricular/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Oxazóis/farmacologia , MasculinoRESUMO
Infections with methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly serious, making the development of novel antimicrobials urgent. Here, we synthesized some amphiphilic honokiol derivatives bearing an oxazole moiety and investigated their antibacterial and hemolytic activities. Bioactivity evaluation showed that E17 possessed significant in vitro antibacterial activity against S. aureus and MRSA, along with low hemolytic activity. Moreover, E17 exhibited rapid bactericidal properties and was not susceptible to resistance. Mechanistic studies indicated that E17 interacts with phosphatidylglycerol and cardiolipin of bacterial cell membranes, leading to changes in cell membrane permeability and polarization, increased intracellular ROS, and leakage of DNA and proteins, thus accelerating bacterial death. Transcriptome analysis further demonstrated that E17 has membrane-targeting effects, affecting the expression of genes related to cell membranes and ABC transporter proteins. Notably, in vivo activity showed that E17 has prominent anti-MRSA efficacy, comparable to vancomycin, and is expected to be a new anti-MRSA drug candidate.
Assuntos
Antibacterianos , Compostos de Bifenilo , Lignanas , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Oxazóis , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Lignanas/química , Lignanas/síntese química , Oxazóis/farmacologia , Oxazóis/química , Oxazóis/síntese química , Animais , Hemólise/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Relação Estrutura-Atividade , Humanos , Camundongos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Compostos Alílicos , FenóisRESUMO
By using a scaffold hopping/ring equivalent and intermediate derivatization strategies, a series of compounds of 2,5-diphenyl-1,3-oxazoline with substituent changes at the 5-phenyl position were prepared, and their acaricidal activity was studied. However, the synthesized 2,5-diphenyl-1,3-oxazolines showed lower activity against mite eggs and larvae compared to the 2,4-diphenyl-1,3-oxazolines with the same substituents. We speculate that there is a significant difference in the spatial extension direction of the substituents between the two skeletons of compounds, resulting in differences in their ability to bind to the potential target chitin synthase 1. This work is helpful in inferring the internal structure of chitin synthase binding pockets.
Assuntos
Acaricidas , Oxazóis , Acaricidas/química , Acaricidas/farmacologia , Acaricidas/síntese química , Animais , Oxazóis/química , Oxazóis/síntese química , Oxazóis/farmacologia , Desenho de Fármacos , Relação Estrutura-Atividade , Ácaros/efeitos dos fármacos , Estrutura Molecular , Larva/efeitos dos fármacos , Quitina Sintase/antagonistas & inibidores , Quitina Sintase/metabolismoRESUMO
BACKGROUND: New and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection. METHODS: Treatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months. RESULTS: B25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens. CONCLUSIONS: BDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy.
Assuntos
Antituberculosos , Diarilquinolinas , Modelos Animais de Doenças , Quimioterapia Combinada , Camundongos Endogâmicos BALB C , Moxifloxacina , Mycobacterium tuberculosis , Nitroimidazóis , Oxazóis , Animais , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Nitroimidazóis/farmacologia , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Camundongos , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Oxazóis/farmacologia , Moxifloxacina/uso terapêutico , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacologia , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Oxazolidinonas/uso terapêutico , Oxazolidinonas/administração & dosagem , Oxazolidinonas/farmacocinética , Pirazinamida/uso terapêutico , Pirazinamida/administração & dosagem , Resultado do Tratamento , IsoxazóisRESUMO
Microorganisms of the ESKAPE group pose an enormous threat to human well-being, thus requiring a multidisciplinary approach for discovering novel drugs that are not only effective but utilize an innovative mechanism of action in order to decrease fast developing resistance. A promising but still hardly explored implementation in the "Trojan horse" antibacterial strategy has been recognized in gallium, an iron mimicry species with no known function but exerting a bacteriostatic/bactericidal effect against some representatives of the group. The study herewith focuses on the bacterium A. baumannii and its siderophore acinetobactin in its two isomeric forms depending on the acidity of the medium. By applying the powerful tools of the DFT approach, we aim to delineate those physicochemical characteristics that are of great importance for potentiating gallium's ability to compete with the native ferric cation for binding acinetobactin such as pH, solvent exposure (dielectric constant of the environment), different metal/siderophore ratios, and complex composition. Hence, the provided results not only furnish some explanation of the positive effect of three Ga3+-based anti-infectives in terms of metal cation competition but also shed light on reported in vitro and in vivo observations at a molecular level in regard to gallium's antibacterial effect against A. baumannii.
Assuntos
Acinetobacter baumannii , Antibacterianos , Teoria da Densidade Funcional , Gálio , Testes de Sensibilidade Microbiana , Gálio/química , Gálio/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Oxazóis/química , Oxazóis/farmacologia , Estrutura Molecular , Imidazóis/química , Imidazóis/farmacologiaRESUMO
Personalized cancer vaccines targeting specific neoantigens have been envisioned as one of the most promising approaches in cancer immunotherapy. However, the physicochemical variability of the identified neoantigens limits their efficacy as well as vaccine manufacturing in a uniform format. Herein, we developed a uniform nanovaccine platform based on poly(2-oxazoline)s (POx) to chemically conjugate neoantigen peptides, regardless of their physicochemical properties. This vaccine system could self-assemble into nanoparticles with uniform size (around 50 nm) and improve antigen accumulation as well as infiltration in the lymph node to increase antigen presentation. In vivo vaccination using this system conjugated with three predicted peptide neoantigen peptides from the MC38 tumor cell line induced 100% robust CD8+ T cell responses and superior tumor clearance compared to free peptides. This POx-based vaccine carrier represents a generalizable approach to increase the availability and efficacy of screened neoantigen peptides for a personalized cancer vaccine.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Nanopartículas , Peptídeos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Peptídeos/química , Peptídeos/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/química , Camundongos , Nanopartículas/química , Humanos , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Oxazóis/química , Polímeros/química , Imunoterapia/métodos , NanovacinasRESUMO
The design of biocompatible and biodegradable nanostructures with controlled morphological features remains a predominant challenge in medical research. Stimuli-responsive vesicles offer significant advantages in drug delivery, biomedical applications, and diagnostic techniques. The combination of poly(2-oxazoline)s with biodegradable polymers could provide exceptional biocompatibility properties and be proposed as a versatile platform for the development of new medicines. Therefore, poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2-isopropyl-2-oxazoline) (PiPrOx) possessing a hydroxy terminal group that acts as an initiator for the ring-opening polymerization of d,l-lactide (DLLA) have been utilized in this study. The resulting amphiphilic block polymers were used to create polymersomes, which undergo solvent-dependent reorganization into bowl-shaped vesicles or stomatocytes. By blending PEtOx-b-PDLLA and PiPrOx-b-PDLLA copolymers, a thermoresponsive stomatocyte was generated, where the opening narrowed and irreversibly closed with a slight increase in the temperature. Detailed transmission electron microscopy analysis reveals the formation of both closed and fused stomatocytes upon heating the sample above the critical solution temperature of PiPrOx.
Assuntos
Oxazóis , Oxazóis/química , Materiais Biocompatíveis/química , Polímeros/química , Humanos , Poliaminas/química , Polimerização , Temperatura , Microscopia Eletrônica de Transmissão , DioxanosRESUMO
BACKGROUND: Substantial evidence indicates trace amines can induce vasoconstriction independently of noradrenaline release. However, the mechanism underlying noradrenaline-independent vasoconstrictor responses to trace amines has not yet been established. This study evaluates the role of trace amine-associated receptor 1 (TAAR1) and other biogenic amine receptors in mediating ß-phenylethylamine and the TAAR-1 selective agonist RO5256390-induced vasoconstriction. METHODS: Vasoconstrictor responses to ß-PEA and the TAAR1-selective agonist, RO5256390 were assessed in vitro in endothelium-denuded aortic rings and third-order mesenteric arteries of male Sprague Dawley rats. RESULTS: ß-PEA and RO5256390 induced concentration-dependent vasoconstriction of aortic rings but not third-order mesenteric arteries. Vasoconstrictor responses in aortic rings were insensitive to antagonists of 5-HT. The murine-selective TAAR1 antagonist, EPPTB, had no effect on either ß-PEA or RO5256390-induced vasoconstriction. The α1-adrenoceptor antagonist, prazosin, and the α2-adrenoceptor antagonist, yohimbine, induced a shift of the ß-PEA concentration response curve too small to be ascribed to antagonism of α1-or α2-adrenoceptors, respectively. The α2-adrenoceptor antagonist atipamezole had no effect on ß-PEA or RO5256390-induced vasoconstriction. CONCLUSION: Vasoconstrictor responses to trace amines are not mediated by classical biogenic amine neurotransmitter receptors. Insensitivity of ß-PEA vasoconstrictor responses to EPPTB, may be explained by its low affinity for rat rather than murine TAAR1. Therefore, TAAR1 remains the most likely candidate receptor mediating vasoconstrictor responses to trace amines and that prazosin and yohimbine have low affinity for TAAR1.
Assuntos
Fenetilaminas , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G , Vasoconstrição , Animais , Masculino , Fenetilaminas/farmacologia , Vasoconstrição/efeitos dos fármacos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Artérias Mesentéricas/metabolismo , Aorta/efeitos dos fármacos , Aorta/fisiologia , Aorta/metabolismo , Benzamidas , Oxazóis , PirrolidinasRESUMO
BACKGROUND: Bedaquiline, delamanid and fluoroquinolones are associated with increased QTcF. Whether clofazimine is associated with QTcF prolongation is less clear. METHODS: All patients with rifampicin-resistant TB enrolled between May 2017 and Dec 2019 were included. ECGs were performed at baseline, month 1, month 3 and month 6 for patients treated with conventional regimens, and at additional timepoint for patients treated with bedaquiline, delamanid and short regimen. We estimated the maximum increase of QTcF and constructed cox proportional hazards models to assess factors associated with QTcF≥501ms. RESULTS: Among 321 patients, 59 (18.4%) patients had QTcF≥501ms during a mean follow-up of 242 days (median 189, range 4-1091). The median maximum increase of QTcF was 43.4 ms (IQR 31.3-65.9) in patients treated with clofazimine. Treatment with clofazimine was significantly associated with QTcF≥501ms as compared to without clofazimine (adjusted hazards ratio (adjHR) 4.35, 95% confidence interval (CI) 2.01-9.44). Among patients not treated with bedaquiline and delamanid, those treated with clofazimine and a fluoroquinolone (adjHR 3.43, 95% CI 1.61-7.34) and those treated with clofazimine and high dose moxifloxacin (adjHR 6.54, 95% CI 2.43-17.60) had a significantly higher risk of QTcF≥501ms as compared to those treated with a fluoroquinolone without other QTcF prolonging agents. Four (1.6%) patients had documented ventricular tachycardia, in which one was Torsade de pointes. One patient was found to have sudden death during hospitalization. CONCLUSIONS: Clofazimine was significantly associated with an increased risk of QTcF prolongation. QTcF≥501ms was potentially associated with fatal event and needed to be managed cautiously.
Assuntos
Antituberculosos , Clofazimina , Diarilquinolinas , Síndrome do QT Longo , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Clofazimina/efeitos adversos , Clofazimina/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Síndrome do QT Longo/induzido quimicamente , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Taiwan/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Diarilquinolinas/efeitos adversos , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Eletrocardiografia , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/uso terapêutico , Idoso , Modelos de Riscos ProporcionaisRESUMO
Oogenesis is the central process required to produce viable oocytes in female mammals. It is initiated during embryonic development, and it involves the specification of primordial germ cells (PGCs) and progresses through the activation of the meiotic program, reaching a crucial phase in prophase I before pausing at diplotene around the time of birth. The significance of meiosis, particularly the prophase I stage, cannot be overstated, as it plays a pivotal role in ensuring the formation of healthy gametes, a prerequisite for successful reproduction. While research has explored meiosis across various organisms, understanding how environmental factors, including radiation, drugs, endocrine disruptors, reproductive age, or diet, influence this complex developmental process remains incomplete. In this chapter, we describe an ex vivo culture method to investigate meiotic prophase I and beyond and the disruption of oogenesis by external factors. Using this methodology, it is possible to evaluate the effects of individual xenobiotics by administering chemicals at specific points during oogenesis. This culture technique was optimized to study the effects of two selected endocrine disruptors (vinclozolin and MEHP), demonstrating that vinclozolin exposure delayed meiotic differentiation and MEHP exposure reduced follicle size. This approach also opens avenues for future applications, involving the exploration of established or novel pharmaceutical substances and their influence on essential events during prophase I, such as homologous recombination and chromosome segregation. These processes collectively dictate the ultimate fitness of oocytes, with potential implications for factors relevant to the reproductive age and fertility.
Assuntos
Meiose , Ovário , Animais , Feminino , Camundongos , Ovário/citologia , Meiose/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Oócitos/citologia , Oócitos/efeitos dos fármacos , Prófase Meiótica I/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Oxazóis/farmacologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacosAssuntos
Nitroimidazóis , Oxazóis , Humanos , Oxazóis/administração & dosagem , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Masculino , Feminino , Resultado do Tratamento , Pessoa de Meia-IdadeRESUMO
In this study, porous networks were efficiently prepared by crosslinking hydrophilic poly(2-isopropenyl-2-oxazoline) (PiPOx) with dicarboxylic polyesters (HOOC-PLA-COOH or HOOC-PCL-COOH) in the presence of sodium chloride as a water-soluble porogen. Importantly, by using a relatively simple synthetic protocol, the resulting spongy materials were freely formed to the desired size and shape while maintaining stable dimensions. According to the SEM data, the porous 3D structure can be altered by the pore dimensions, which are dependent on the porogen crystal size. After porosity characterization, the mechanical properties were also evaluated via uniaxial compression and tensile tests. The porous networks formed hydrogels with a high water absorption capacity. Finally, after showing cytocompatibility by the MTT assay, we also demonstrated the applicability of the porous hydrogels as scaffolds for cell cultivation. The presented results suggest that this type of hydrogels is a promising material for tissue engineering.
Assuntos
Materiais Biocompatíveis , Hidrogéis , Poliésteres , Alicerces Teciduais , Hidrogéis/química , Hidrogéis/farmacologia , Porosidade , Alicerces Teciduais/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Poliésteres/química , Regeneração Óssea/efeitos dos fármacos , Engenharia Tecidual , Oxazóis/química , Oxazóis/farmacologia , Humanos , Teste de Materiais , AnimaisRESUMO
Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.
Assuntos
Antituberculosos , Nitroimidazóis , Oxazóis , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Masculino , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Estudos Prospectivos , Rifampina/efeitos adversos , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Antituberculosos/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Idoso , China , Adulto Jovem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologiaRESUMO
Enzymes are known for their remarkable catalytic efficiency across a wide range of applications. Here, we present a novel and convenient nanoreactor platform based on zwitterionic polyelectrolyte complex vesicles (PCVs), assembled from oppositely charged homopoly(2-oxazoline)s, facilitating enzyme immobilization. We show remarkable enhancements in catalytic activity and stability by encapsulation of lipase as a model enzyme. Even as the temperature rises, the performance of the lipase remains robust. Further, the structural characteristics of PCVs, including hollow architecture and semipermeable membranes, endow them with unique advantages for enzyme cascade reactions involving glucose oxidase (GOx) and horseradish peroxidase (HRP). A decline in catalytic efficiency is shown when the enzymes are individually loaded and subsequently mixed, in contrast to the coloaded GOx-HRP-PCV group. We demonstrate that the vesicle structures establish confined environments where precise enzyme-substrate interactions facilitate enhanced catalytic efficiency. In addition, the nanoreactors exhibit excellent biocompatibility and efficient anti-tumor activity, which hold significant promise for biomedical applications within enzyme-based technologies.