RESUMO
The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 µM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 µM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.
Assuntos
Antineoplásicos , Proliferação de Células , Neoplasias Colorretais , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90 , Histona Desmetilases , Organoides , Neoplasias da Próstata , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Animais , Organoides/efeitos dos fármacos , Organoides/patologia , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Peixe-Zebra , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI50 = 0.495 µMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.
RESUMO
Obesity-related functional iron disorder remains a major nutritional challenge. We evaluated the effects of djulis hull (DH) on iron metabolism in 50% high-fat-diet-induced obese rats supplemented with ferric citrate (2 g iron/kg diet) for 12 weeks. DH supplementation (5, 10, 15% dry weight/kg diet) significantly increased serum and hepatic iron but decreased appetite hormones, body weight, hepcidin, and liver inflammation (all p < 0.05). The Spearman correlation showed that appetite hormones were negatively associated with iron but positively correlated with liver hepcidin (all p < 0.05). A Western blot analysis showed that DH significantly downregulated hepatic hepcidin through the IL-6-JAK-STAT3 and enhanced ferroportin (Fpn) via the Keap1-Nrf2 and PHD2-HIF-2α. An in vitro study revealed that major bioactive compounds of DH, hexacosanol, and squalene suppressed LPS-induced IL-6 and hepcidin but enhanced Fpn expression in activated THP-1 cells. In conclusion, DH may exert nutraceutical properties for the treatment of functional iron disorder and restoration of iron efflux may have beneficial effects on weight control.
Assuntos
Hepcidinas , Interleucina-6 , Ratos , Animais , Hepcidinas/genética , Hepcidinas/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ferro/metabolismo , Obesidade/tratamento farmacológico , Obesidade/etiologia , Suplementos Nutricionais , HormôniosRESUMO
Cancer vaccines have recently garnered tremendous interest. However, the targeted delivery of antigens and adjuvants to dendritic cells (DCs) still remains challenging. In this study, we developed glycosylated poly(lactic-co-glycolic acid) nanoparticles (NPs) loaded with the SIINFEKL peptide (OVA) as a tumor-specific antigen and CpG oligodeoxynucleotide (CpG) as an adjuvant for an effective DC-targeted cancer vaccine. Surface modification of NPs with galactose (Gal) or mannose (Man) was carried out by a double-emulsion solvent evaporation method, and the products were respectively named OVA-CpG Gal-NPs and OVA-CpG Man-NPs. They exhibited a uniform particle size, high loading capacity, robust stability, and extended release. The OVA-CpG Gal-NPs were found to rapidly enhance antigen uptake and DC maturation. In the in vivo study, OVA-CpG Gal-NPs via intravenous (i.v.), intranasal (i.n.) and subcutaneous (s.c.) routes had rapidly accumulated in the spleen. Moreover, the non-glycosylated OVA-CpG NPs after s.c. immunization could rapidly be trafficked to distal lymph nodes and sustained higher levels. All of these formulations increased the level of cluster of differentiation 4-positive (CD4+) T cells and interferon (IFN)-γ in the spleen, then promoted the cytotoxic CD8+ tumor-infiltrating lymphocytes against E.G7-OVA lymphomas. In conclusion, galactosylated NPs provided an effective platform to enhance the DC targeting to induce cellular immunity and T-cell recruitment into tumor sites in vivo, thus showing great potential to be developed as a prophylactic vaccine for cancer immunotherapy.
Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Humanos , Animais , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Glicosilação , Ovalbumina , Adjuvantes Imunológicos , Antígenos de Neoplasias/metabolismo , Vacinação , Neoplasias/prevenção & controle , Células Dendríticas , Camundongos Endogâmicos C57BLRESUMO
Anticipation is the phenomenon in which the response of a system is predictive of the stimulation. The encoding of stochastic light intensity (x) into spikes is investigated in an experiment with retinas from bullfrogs to understand the mechanism of anticipation of a retina. Partial information decomposition of the mutual information between the spike rates and the joint state {x,x[over Ì]} is found to be consistent with the encoding by the linear combination of x and x[over Ì] where x[over Ì] is the rate of change of x. This spike rate encoding form indicates that a retina is capable of anticipation based on the synergistic information generation between x and x[over Ì]. Our results suggest that illusions such as the anticipation studied here during retinal perception can originate from the recombination of information extracted in the retinal network.
RESUMO
The mechanism of negative group delay (NGD) is used to understand the anticipatory capability of a retina. Experiments with retinas from bullfrogs are performed to compare with the predictions of the NGD model. In particular, whole field stochastic stimulations with various autocorrelation times are used to probe anticipatory responses from the retina. We find that the NGD model can reproduce essential features of experimental observations characterized by the cross correlations between the stimulation and the retinal responses. Experiments with dark light pulse stimulations further support the NGD mechanism, with the retina producing time-advanced pulse responses. However, no time-advanced pulse responses are produced by bright pulses. Counterintuitively, the NGD model shows that it is the delay in the system which gives rise to anticipation because of the negative feedback adaptation mechanism.
Assuntos
Retina/fisiologia , Luz , Estimulação LuminosaRESUMO
Effects of mechanical coupling on cardiac dynamics are studied by monitoring the beating dynamics of a cardiac tissue which is being pulled periodically at a pace slower than its intrinsic beating rate. The tissue is taken from the heart of a bullfrog that includes pacemaker cells. The cardiac tissue beats spontaneously with an almost constant interbeat interval (IBI) when there is no external forcing. On the other hand, the IBI is observed to vary significantly under an external periodic drive. Interestingly, when the period of the external drive is about two times the intrinsic IBI of the tissue without pulling, the IBI as a function of time exhibits a wave packet structure. Our experimental results can be understood theoretically by a phase-coupled model under external driving. In particular, the theoretical prediction of the wave-packet period as a function of the normalized driving period agrees excellently with the observations. Furthermore, the cardiac mechanical coupling constant can be extracted from the experimental data from our model and is found to be insensitive to the external driving period. Implications of our results on cardiac physiology are also discussed.
Assuntos
Relógios Biológicos , Coração/fisiologia , Fenômenos Mecânicos , Miocárdio/citologia , Animais , Fenômenos Biomecânicos , Cinética , Modelos Cardiovasculares , Rana catesbeianaRESUMO
The aim of the present study was to prepare sublingual delivery systems for sildenafil and evaluate its relative bioavailability after sublingual administration in rabbits to attain a rapid onset of action with good efficacy at lower doses. For sublingual application, sildenafil and its citrate were formulated in 2 different dosage forms: the first was a sublingual spray consisting of sildenafil in 2 microemulsion systems, oleic acid or propylene glycol (PG), and the second was sublingual tablets prepared with various granulated sublingual sprays adsorbed onto a silicate adsorbant (Florite(®) R), binders (Cyclocel(®) or EMDEX(®)), and disintegrants (Ac-Di-Sol(®) or Kollidon(®) CL). Results showed that sublingual absorption of sildenafil spray prepared with PG was fairly rapid. At a 0.5-mg dose, the mean onset of action was 1.3 ± 0.6 min and lasted for about 1.5 h according to the pharmacokinetic studies. In vivo studies also showed that for sublingual tablets formulated with sildenafil in PG adsorbed onto Florite(®) R at a 1:1 weight ratio then mixed with Cycloel(®) and Ac-Di-Sol(®), the onset action was fast at 1.9 ± 0.4 min and lasted for about 1 h at 0.5 mg. These findings suggest the potential for the sublingual delivery of sildenafil instead of the conventional oral administration.
Assuntos
Citrato de Sildenafila/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Sublingual , Animais , Disponibilidade Biológica , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Excipientes , Dureza , Masculino , Ácido Oleico , Veículos Farmacêuticos , Propilenoglicol , Coelhos , Citrato de Sildenafila/farmacocinética , Solubilidade , Comprimidos , Vasodilatadores/farmacocinéticaRESUMO
An oleic acid-based microemulsion system with a member of the Tween series or Cremophor EL as the surfactant and a short-chain alcohol as the cosolvent was developed for rapid-onset intranasal delivery of sildenafil. The phase behaviour and solubilization capacity of the microemulsion system were characterized, and nasal absorption of sildenafil from the microemulsion formulations was investigated in rabbits. Sildenafil displayed a high solubility of 124 mg/mL in the microemulsion consisting of 40% oleic acid, 10% H(2)O, and 50% Tween 80:ethanol (EA) (at a 1:4 weight ratio). Nasal absorption of sildenafil from this microemulsion was found to be fairly rapid. With a 10-mg dose, the onset of action was arrived instantly following intranasal administration and the duration was over 3 h using an in vivo rabbit studies. In addition, nasal ciliotoxicity studies were carried out using in vivo rat nasal mucosa model and showed no ciliotoxicity. Therefore, the prepared systems are no serious nasal ciliotoxicity for intranasal administration. The microemulsion system composed of oleic acid, Tween 80, EA, and water may be a practical approach for the rapid-onset delivery of sildenafil for the treatment of erectile dysfunction.