RESUMO
Objective: Preoperative obstructive sleep apnea (OSA) is supposed to be the abnormally high occurrence of OSA the night before surgery under general anesthesia. This study aimed to evaluate the prevalence preoperative OSA using cardiopulmonary coupling (CPC) and its correlation with imbalance of sympathetic/parasympathetic nervous system. Methods: A total of 550 patients with plans to receive surgery under general anesthesia were enrolled. All patients were assigned to wear CPC on the night before surgery until the next day. Sleep quality characteristics, heart rate variation parameters, and apnea-hypopnea index were acquired. The diagnosis of pre-existing OSA was not considered in the current study. Results: According to apnea-hypopnea index, 28.4%, 32.2%, 26.2%, and 13.3% patients were assessed as no, mild, moderate, and severe operative OSA, respectively. Multivariate logistic regression model revealed that higher age [p < 0.001, odds ratio (OR) = 1.043] was independently and positively associated with preoperative OSA; heart rate variation parameters representing the imbalance of sympathetic/parasympathetic nervous system, such as higher low-frequency (p < 0.001, OR = 1.004), higher low-frequency/high-frequency ratio (p = 0.028, OR = 1.738), lower NN20 count divided by the total number of all NN intervals (pNN20; p < 0.001, OR = 0.950), and lower high-frequency (p < 0.001, OR = 0.998), showed independent relationships with a higher probability of preoperative OSA. Higher age (p = 0.005, OR = 1.024), higher very-low-frequency (p < 0.001, OR = 1.001), and higher low-frequency/high-frequency ratio (p = 0.003, OR = 1.655) were associated with a higher probability of moderate-to-severe preoperative OSA, but higher pNN10 (p < 0.001, OR = 0.951) was associated with a lower probability of moderate-to-severe preoperative OSA. Conclusion: Preoperative OSA is prevalent. Higher age and imbalance of sympathetic/parasympathetic nervous system are independently and positively associated with a higher occurrence of preoperative OSA. CPC screening may promote the management of preoperative OSA.
RESUMO
Autophagy mediates PM2.5-related lung injury (LI) and is tightly linked to inflammation and apoptosis processes. IL-37 has been demonstrated to regulate autophagy. This research aimed to examine the involvement of IL-37 in the progression of PM2.5-related LI and assess whether autophagy serves as a mediator for its effects.To create a model of PM2.5-related LI, this research employed a nose-only PM2.5 exposure system and utilized both human IL-37 transgenic mice and wild-type mice. The hIL-37tg mice demonstrated remarkable reductions in pulmonary inflammation and pathological LI compared to the WT mice. Additionally, they exhibited activation of the AKT/mTOR signaling pathway, which served to regulate the levels of autophagy and apoptosis.Furthermore, in vitro experiments revealed a dose-dependent upregulation of autophagy and apoptotic proteins following exposure to PM2.5 DMSO extraction. Simultaneously, p-AKT and p-mTOR expression was found to decrease. However, pretreatment with IL-37 demonstrated a remarkable reduction in the levels of autophagy and apoptotic proteins, along with an elevation of p-AKT and p-mTOR. Interestingly, pretreatment with rapamycin, an autophagy inducer, weakened the therapeutic impact of IL-37. Conversely, the therapeutic impact of IL-37 was enhanced when treated with 3-MA, a potent autophagy inhibitor. Moreover, the inhibitory effect of IL-37 on autophagy was successfully reversed by administering AKT inhibitor MK2206. The findings suggest that IL-37 can inhibit both the inflammatory response and autophagy, leading to the alleviation of PM2.5-related LI. At the molecular level, IL-37 may exert its anti autophagy and anti apoptosis effects by activating the AKT/mTOR signaling pathway.
Assuntos
Lesão Pulmonar , Material Particulado , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Autofagia/efeitos dos fármacos , Interleucinas/farmacologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Material Particulado/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Injectable hydrogels have previously demonstrated potential as a temporary scaffold for tissue regeneration or as a delivery vehicle for cells, growth factors, or drugs. However, most injectable hydrogel systems lack a microporous structure, preventing host cell migration into the hydrogel interior and limiting spreading and proliferation of encapsulated cells. Herein, an injectable microporous hydrogel assembled from gelatin/gelatin methacryloyl (GelMA) composite microgels is described. Microgels are produced by a water-in-oil emulsion using a gelatin/GelMA aqueous mixture. These microgels show improved thermal stability compared to GelMA-only microgels and benefit from combined photopolymerization using UV irradiation (365 nm) in the presence of a photoinitiator (PI) and enzymatic reaction by microbial transglutaminase (mTG), which together enable fast curing and tissue adhesion of the hydrogel. The dual-crosslinking approach also allows for the reduction of PI concentration and minimizes cytotoxicity during photopolymerization. When applied for in situ cell encapsulation, encapsulated human dermal fibroblasts and human mesenchymal stem cells (hMSCs) are able to rapidly spread and proliferate in the pore space of the hydrogel. This hydrogel has the potential to enhance hMSC anti-inflammatory behavior through the demonstrated secretion of prostaglandin E2 (PGE2) and interleukin-6 (IL-6) by encapsulated cells. Altogether, this injectable formulation has the potential to be used as a cell delivery vehicle for various applications in regenerative medicine.
Assuntos
Células-Tronco Mesenquimais , Microgéis , Encapsulamento de Células , Gelatina/química , Humanos , Hidrogéis/química , Metacrilatos , Engenharia TecidualRESUMO
Epigenetic regulation of gene expression is an emerging target to treat several human diseases including cancers. In cancers, expressions of many tumor suppressor genes are suppressed by hyper-methylation in their regulatory regions. Herein, we describe a novel carbazole SH-I-14 that decreased the level of the acetyl-STAT3 at the K685 residue. Mutation analysis revealed that SH-I-14 disrupted STAT3-DNMT1 interaction by removing acetyl group from K685 of STAT3. Finally, the inhibition of STAT3-DNMT1 interaction by SH-I-14 resulted in re-expression of tumor suppressor genes such as VHL and PDLIM4 through de-methylation of their promoter regions. In addition, SH-I-14 showed anti-proliferative effect in triple-negative breast cancer (TNBC) cell lines in vitro and anti-tumor effect in a mouse xenograft model of MDA-MB-231 tumor. Taken together, our results suggest that targeting acetyl-STAT3 (K685) provides potential therapeutic opportunity to treat a subset of human cancers.
RESUMO
The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.
Assuntos
Benzopiranos/uso terapêutico , Estilbenos/uso terapêutico , Nanomedicina Teranóstica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Estilbenos/química , Estilbenos/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Moduladores de TubulinaRESUMO
The aberrant activation of STAT3 occurs in many human cancers and promotes tumor progression. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3. Synthesized carbazole derived with fluorophore compound 12 was discovered to target STAT3 phosphorylation. Compound 12 was found to inhibit STAT3-mediated transcription as well as to reduce IL-6 induced STAT3 phosphorylation in cancer cell lines expressing both elevated and low levels of phospho-STAT3 (Y705). Compound 12 potently induced apoptosis in a broad number of TNBC cancer cell lines in vitro and was effective at inhibiting the in vivo growth of human TNBC xenograft tumors (SUM149) without any observed toxicity. Compound 12 also effectively inhibited the growth of human lung tumor xenografts (A549) harboring aberrantly active STAT3. In vitro and in vivo studies showed that the inhibitory effects of 12 on phospho-STAT3 were through up-regulation of the protein-tyrosine phosphatase PTPN6. Our present studies strongly support the continued preclinical evaluation of compound 12 as a potential chemotherapeutic agent for TNBC and cancers with constitutive STAT3 signaling.
Assuntos
Antineoplásicos/química , Carbazóis/química , Naftalenossulfonatos/química , Proteína Tirosina Fosfatase não Receptora Tipo 6/biossíntese , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carbazóis/síntese química , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Indução Enzimática , Feminino , Xenoenxertos , Humanos , Interleucina-6/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftalenossulfonatos/síntese química , Naftalenossulfonatos/farmacologia , Transplante de Neoplasias , Fosforilação , Relação Estrutura-Atividade , Transcrição GênicaRESUMO
This study is to investigate the effect of Icogenin on and its mechanism in anti-metastasis of pancreatic cancer BxPC3 cells in vitro. Using transwell assay, the effects of Icogenin on the invasion of BxPC3 cells were measured. The abilities of cell motility and adhesion in BxPC3 cells were detected by MTT assay and wound healing assay, respectively. The MAPK signal pathway protein expressions were analyzed with Western blotting. Also, the activity of MMP2 was observed by zymography assay. Icogenin inhibited the abilities of motility, adhesion and invasion of pancreatic cancer BxPC3 cells in vitro (P < 0.05), in a dose-depended manner, and inhibited the secretion of MMP2 and phosphorylation of ERK. PD98059 and U0126 which were ERK inhibitors could suppress the abilities of invasion and metastasis of pancreatic cancer BxPC3 cells. It is concluded that Icogenin can inhibit the abilities of invasion and metastasis of pancreatic cancer in vitro by inhibiting the secretion of MMP2 and phosphorylation of ERK.
Assuntos
Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Pancreáticas/patologia , Saponinas/farmacologia , Esteroides/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Dracaena/química , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica , Neoplasias Pancreáticas/metabolismo , Fosforilação , Saponinas/isolamento & purificação , Transdução de Sinais , Esteroides/isolamento & purificaçãoRESUMO
Natural saponin icogenin, namely 25(S)-22-O-methyl-furost-5-en-3beta,26-dio-3-O-alpha-L-rhamnopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->3)]-beta-D-glucopyranoside, and one of its analogues, 25(S)-22-O-methyl-furost-5-en-3beta,26-dio-3-O-alpha-L-rhamnopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->3)]-alpha-D-glucopyranoside, were first synthesized via line strategy and convergent approach, respectively. It was observed that icogenin and its analogue show potent antitumor activity in vitro.