RESUMO
Dry age-related macular degeneration (AMD) is a prevalent clinical condition that leads to permanent damage to central vision and poses a significant threat to patients' visual health. Although the pathogenesis of dry AMD remains unclear, there is consensus on the role of retinal pigment epithelium (RPE) damage. Oxidative stress and chronic inflammation are major contributors to RPE cell damage, and the NOD-like receptor thermoprotein structural domain-associated protein 3 (NLRP3) inflammasome mediates the inflammatory response leading to apoptosis in RPE cells. Furthermore, lipofuscin accumulation results in oxidative stress, NLRP3 activation, and the development of vitelliform lesions, a hallmark of dry AMD, all of which may contribute to RPE dysfunction. The process of autophagy, involving the encapsulation, recognition, and transport of accumulated proteins and dead cells to the lysosome for degradation, is recognized as a significant pathway for cellular self-protection and homeostasis maintenance. Recently, RPE cell autophagy has been discovered to be closely linked to the development of macular degeneration, positioning autophagy as a cutting-edge research area in the realm of dry AMD. In this review, we present an overview of how lipofuscin, oxidative stress, and the NLRP3 inflammasome damage the RPE through their respective causal mechanisms. We summarized the connection between autophagy, oxidative stress, and NLRP3 inflammatory cytokines. Our findings suggest that targeting autophagy improves RPE function and sustains visual health, offering new perspectives for understanding the pathogenesis and clinical management of dry AMD.
Assuntos
Autofagia , Estresse Oxidativo , Epitélio Pigmentado da Retina , Humanos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Autofagia/fisiologia , Estresse Oxidativo/fisiologia , Inflamassomos/metabolismo , Lipofuscina/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Atrofia Geográfica/metabolismo , Atrofia Geográfica/patologiaRESUMO
Acetone is an essential indicator for determining the aging of transformer insulation. Rapid, sensitive, and accurate quantification of acetone in transformer oil is highly significant in assessing the aging of oil-paper insulation systems. In this study, silver nanowires modified with small zinc oxide nanoparticles (ZnO NPs@Ag NWs) were excellent surface-enhanced Raman scattering (SERS) substrates and efficiently and sensitively detected acetone in transformer oil. Stoichiometric models such as multiple linear regression (MLR) models and partial least square regressions (PLS) were investigated to quantify acetone in transformer oil and compared with commonly used univariate linear regressions (ULR). PLS combined with a preprocessing algorithm provided the best prediction model, with a correlation coefficient of 0.998251 for the calibration set, 0.997678 for the predictive set, a root mean square error in the calibration set (RMSECV = 0.12596 mg/g), and a prediction set (RMSEP = 0.11408 mg/g). For an acetone solution of 0.003 mg/g, the mean absolute percentage error (MAPE) was the lowest among the three quantitative models. For a concentration of 7.29 mg/g, the MAPE was 1.60%. This method achieved limits of quantification and detections of 0.003 mg/g and 1 µg/g, respectively. In general, these results suggested that ZnO NPs@Ag NWs as SERS substrates coupled with PLS simply and accurately quantified trace acetone concentrations in transformer oil.
Assuntos
Nanopartículas Metálicas , Nanofios , Óxido de Zinco , Prata , Acetona , Análise Espectral Raman/métodosRESUMO
TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-reactivation and induction of massive apoptosis-1) and its methylated analogue PRIMA-1Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53. Herein we report that piperlongumine (PL), an alkaloid isolated from Piper longum L., synergizes with APR-246 to selectively induce apoptosis and autophagic cell death in HNSCC cells, whereas primary and immortalized mouse embryonic fibroblasts and spontaneously immortalized non-tumorigenic human skin keratinocytes (HaCat) are spared from the damage by the co-treatment. Interestingly, PL-sensitized HNSCC cells to APR-246 are TP53 mutation-independent. Instead, we demonstrated that glutathione S-transferase pi 1 (GSTP1), a GST family member that catalyzes the conjugation of GSH with electrophilic compounds to fulfill its detoxification function, is highly expressed in HNSCC tissues. Administration of PL and APR-246 significantly suppresses GSTP1 activity, resulting in the accumulation of ROS, depletion of GSH, elevation of GSSG, and DNA damage. Ectopic expression of GSTP1 or pre-treatment with antioxidant N-acetyl-L-cysteine (NAC) abrogates the ROS elevation and decreases DNA damage, apoptosis, and autophagic cell death prompted by PL/APR-246. In addition, administration of PL and APR-246 impedes UMSCC10A xenograft tumor growth in SCID mice. Taken together, our data suggest that HNSCC cells are selectively sensitive to the combination of PL and APR-246 due to a remarkably synergistic effect of the co-treatment in the induction of ROS by suppression of GSTP1.
Assuntos
Carcinoma de Células Escamosas/patologia , Dioxolanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa S-Transferase pi/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Quinuclidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Quimioterapia Combinada , Feminino , Seguimentos , Glutationa S-Transferase pi/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Camundongos , Camundongos SCID , Prognóstico , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The AMP-activated protein kinase (AMPK) plays critical roles in growth regulation and metabolism reprogramming. AMPK activation protects cells against apoptosis from injury in different cell and animal models. However, its function in necroptosis remains largely unclear. METHODS AND RESULTS: In the current study, we demonstrated that AMPK was activated upon necroptosis induction and protected mouse embryonic fibroblasts (MEFs) and cardiomyocytes from N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and reactive oxygen species (ROS) induced necroptosis. Activation of AMPK with chemicals A-769662, 2-deoxyglucose (2-DG), and metformin or constitutively active (CA) AMPK markedly decreased necroptosis and cytotoxicity induced by MNNG. In contrast, AMPK inhibitor compound C, dominant negative (DN) AMPK, as well as AMPK shRNAs increased necroptosis and cytotoxicity induced by MNNG. We further showed that AMPK physically associated with a protein complex containing PGAM5 and Keap1 whereby facilitating Keap1-mediated PGAM5 ubiquitination upon necroptosis induction. The AMPK agonist metformin ameliorated myocardial ischemia and reperfusion (IR) injury and reduced necroptosis through down-regulating the expression of PGAM5 in the Langendorff-perfused rat hearts. CONCLUSION: Activation of AMPK protects against necroptosis via promoting Keap1-mediated PGAM5 degradation. Metformin may act as a valuable agent for the protection of myocardial ischemia and reperfusion injury by activating AMPK and reducing necroptosis.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/fisiologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Animais , Linhagem Celular , Ativação Enzimática/fisiologia , Preparação de Coração Isolado/métodos , Masculino , Camundongos , Camundongos Knockout , Necrose/metabolismo , Necrose/patologia , Necrose/prevenção & controle , Ratos , Ratos Sprague-DawleyRESUMO
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53. In the current report, we demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) with 6(5H)-phenanthridinone (PHEN) and N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N, N-dimethylamino) acetamide hydrochloride (PJ34) sensitizes UMSCC1, UMSCC14, and UMSCC17A, three HNSCC cell lines to the treatment of APR-246. PHEN enhances APR-246-induced apoptosis, but not programmed necrosis or autophagic cell death in HNSCC cells. The PARP-1 inhibition-induced sensitization of HNSCC cells to APR-246 is independent of TP53 mutation. Instead, PARP-1 inhibition promotes APR-246-facilitated inactivation of thioredoxin reductase 1 (TrxR1), leading to ROS accumulation and DNA damage. Overexpression of TrxR1 or application of antioxidant N-acetyl-L-cysteine (NAC) depletes the ROS increase, reduces DNA damage, and decreases cell death triggered by APR-246/PHEN in HNSCC cells. Thus, we have characterized a new function of PARP-1 inhibitor in HNSCC cells by inactivation of TrxR1 and elevation of ROS and provide a novel therapeutic strategy for HNSCC by the combination of PARP-1 inhibitors and APR-246.
RESUMO
OBJECTIVE: To study on clinical significance of acoustic rhinometry and nasal resistance checks by low temperature radiofrequency ablation on nasal endoscopy operation. METHOD: Application instrument of acoustic rhinometry and nasal resistance meter on 106 cases with moderate to severe persistent nasal obstruction symptoms. These patients are not obvious or invalid after regular drug treatment. The preoperative and postoperative six months, with the nasal mucosa contraction before and after by inspect respectively,also record nasal resistance (NR), nasal minimum cross-sectional area (NMCA), distance of the minimal cross-sectional area to the nostril (DCAN), mean nasal cross-sectional area (MNCA), nasal cavity from volume (NCV). The other 36 cases of healthy people as a control group. Before and after nasal mucosa contraction by inspect. Two sets of data were statistically analyzed with SAS6.12. The efficacy evaluation of radiofrequency ablation by improve the extent and visual analog scale (VAS) score, with the patient's subjective symptoms. RESULT: The group of preoperative rhinitis treatment NR higher than the controls significantly, the NMCA significantly lower than the control group (P< 0.01). The group of postoperative by radiofrequency ablation and rhinitis treatment was 100%, postoperative VAS scores were decreased compared with pre operative (P < 0.01). The group of rhinitis treatment NR was significantly lower than the preoperative, and NMCA significantly increased compared with the preoperative (P < 0.01). Before and after nasal contraction in the same group, NR and NMCA was no difference (P > 0.05). The NR and NMCA of the postoperative in rhinitis treatment group was no difference compared with the control group (P > 0.05). CONCLUSION: Low temperature radio frequency ablation by nasal endoscopy operation had a significant improvement of nasal ventilation functions for patients with moderate to severe chronic rhinitis, acoustic rhinometry and nasal resistance can be an objective and accurate evaluation to this operation.