RESUMEN
Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world, which is frequently diagnosed at a late stage. HCC patients have a poor prognosis due to the lack of an efficacious therapeutic strategy. Approved drug repurposing is a way for accelerating drug discovery and can significantly reduce the cost of drug development. Carfilzomib (CFZ) is a second-generation proteasome inhibitor, which is highly efficacious against multiple myeloma and has been reported to possess potential antitumor activities against multiple cancers. However, the underlying mechanism of CFZ on HCC is still unclear. Here, we show that CFZ inhibits the proliferation of HCC cells through cell cycle arrest at the G2/M phase and suppresses the migration and invasion of HCC cells by inhibiting epithelial-mesenchymal transition. We also find that CFZ promotes reactive oxygen species production to induce endoplasmic reticulum (ER) stress and activate JNK/p38 MAPK signaling in HCC cells, thus inducing cell death in HCC cells. Moreover, CFZ significantly inhibits HCC cell growth in a xenograft mouse model. Collectively, our study elucidates that CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling, thus inhibiting HCC cell and tumor growth. This indicates that CFZ has the potential as a therapeutic drug for HCC.
Asunto(s)
Apoptosis , Carcinoma Hepatocelular , Estrés del Retículo Endoplásmico , Neoplasias Hepáticas , Oligopéptidos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Oligopéptidos/farmacología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ratones , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
Approximately 50 million people are suffering from epilepsy worldwide. Corals have been used for treating epilepsy in traditional Chinese medicine, but the mechanism of this treatment is unknown. In this study, we analyzed the transcriptome of the branching coral Acropora digitifera and obtained its Kyoto Encyclopedia of Genes and Genomes (KEGG), EuKaryotic Orthologous Groups (KOG) and Gene Ontology (GO) annotation. Combined with multiple sequence alignment and phylogenetic analysis, we discovered three polypeptides, we named them AdKuz1, AdKuz2 and AdKuz3, from A. digitifera that showed a close relationship to Kunitz-type peptides. Molecular docking and molecular dynamics simulation indicated that AdKuz1 to 3 could interact with GABAA receptor but AdKuz2-GABAA remained more stable than others. The biological experiments showed that AdKuz1 and AdKuz2 exhibited an anti-inflammatory effect by decreasing the aberrant level of nitric oxide (NO), IL-6, TNF-α and IL-1ß induced by LPS in BV-2 cells. In addition, the pentylenetetrazol (PTZ)-induced epileptic effect on zebrafish was remarkably suppressed by AdKuz1 and AdKuz2. AdKuz2 particularly showed superior anti-epileptic effects compared to the other two peptides. Furthermore, AdKuz2 significantly decreased the expression of c-fos and npas4a, which were up-regulated by PTZ treatment. In addition, AdKuz2 reduced the synthesis of glutamate and enhanced the biosynthesis of gamma-aminobutyric acid (GABA). In conclusion, the results indicated that AdKuz2 may affect the synthesis of glutamate and GABA and enhance the activity of the GABAA receptor to inhibit the symptoms of epilepsy. We believe, AdKuz2 could be a promising anti-epileptic agent and its mechanism of action should be further investigated.
Asunto(s)
Antozoos , Animales , Antozoos/química , Antozoos/genética , Anticonvulsivantes/farmacología , Glutamatos/genética , Humanos , Simulación del Acoplamiento Molecular , Pentilenotetrazol , Péptidos/genética , Filogenia , Receptores de GABA-A/genética , Transcriptoma , Pez Cebra/genética , Ácido gamma-AminobutíricoRESUMEN
6-benzylaminopurine (6-BA), classified as a "plant hormone", is an important ingredient in production of "toxic bean sprouts". Although there is no direct evidence of adverse effects, its hazardous effects have received some attention and aroused furious debate between proponents and environmental regulators. In this study, potential adverse effects of 6-BA were investigated by exposing zebrafish in vivo to 0.2 - 25 mg 6-BA/L. Results indicated that, when exposure was limited to early-life stage (4-36 hpf), 20 mg 6-BA/L caused early hatching, abnormal spontaneous movement, and precocious hyperactivity in zebrafish embryos/larvae. While under a continuous exposure regime, 6-BA at 0.2 mg/L was able to cause hyperactive locomotion and transcription of genes related to neurogenesis (gnrh3 and nestin) and endocrine systems (cyp19a and fshb) in 5 dpf larvae. Quantification by use of LC/MS indicated bioaccumulation of 6-BA in zebrafish increased when exposed to 0.2 or 20 mg 6-BA/L. These results suggested that 6-BA could accumulate in aquatic organisms and disrupt neuro-endocrine systems. Accordingly, exposure to 0.2 mg 6-BA/L increased production of estradiol (E2) and consequently E2/T ratio in zebrafish larvae, which directly indicated 6-BA is estrogenic. In silico simulations demonstrated potential for binding of 6-BA to estrogen receptor alpha (ERa) and cytochrome P450 aromatase (CYP19A). Therefore, induction of estrogenic effects, via potential interactions with hormone receptors or disturbance of downstream transcription signaling, was possible mechanism underlying the toxicity of 6-BA. Taken together, these findings demonstrate endocrine disrupting properties of 6-BA, which suggest concerns about risks posed to endocrine systems.
Asunto(s)
Disruptores Endocrinos , Contaminantes Químicos del Agua , Animales , Compuestos de Bencilo/toxicidad , Disruptores Endocrinos/metabolismo , Disruptores Endocrinos/toxicidad , Sistema Endocrino/metabolismo , Purinas , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Herpes simplex virus type 1 (HSV-1)-mediated oncolytic therapy is a promising cancer treatment modality. However, viral tropism is considered to be one of the major stumbling blocks to the development of HSV-1 as an anticancer agent. METHODS: The surface of oncolytic HSV-1 G207 was covalently modified with folate-poly (ethylene glycol) conjugate (FA-PEG). The specificities and tumor targeting efficiencies of modified or unmodified G207 particles were analyzed by a real-time polymerase chain reaction at the level of cell attachment and entry. Immune responses were assessed by an interleukin-6 release assay from RAW264.7 macrophages. Biodistribution and in vivo antitumoral activity after intravenous delivery was evaluated in BALB/c nude mice bearing subcutaneous KB xenograft tumors. RESULTS: FA-PEG-HSV exhibited enhanced targeting specificity for folate receptor over-expressing tumor cells and had lower immunogenicity than the unmodified HSV. In vivo, the FA-PEG-HSV group revealed an increased anti-tumor efficiency and tumor targeting specificity compared to the naked HSV. CONCLUSIONS: These results indicate that folate-conjugated HSV G207 presents a folate receptor-targeted oncolytic virus with a potential therapeutic value via retargeting to tumor cells.
Asunto(s)
Ácido Fólico/análogos & derivados , Ácido Fólico/química , Herpesvirus Humano 1 , Viroterapia Oncolítica/métodos , Polietilenglicoles/química , Células A549 , Administración Intravenosa , Animales , Línea Celular Tumoral , Chlorocebus aethiops , Receptores de Folato Anclados a GPI/química , Humanos , Inmunidad , Interleucina-6/metabolismo , Células KB , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células RAW 264.7 , Distribución Tisular , Células Vero , Internalización del VirusRESUMEN
Epilepsy is a chronic neurological disorder, characterized by recurrent, spontaneous, and transient seizures, and affects more than 70 million people worldwide. Although two dozen antiepileptic drugs (AEDs) are approved and available in the market, seizures remain poorly controlled in one-third of epileptic patients who are suffering from drug resistance or various adverse effects. Recently, the xanthone skeleton has been regarded as an attractive scaffold for the discovery and development of emerging anticonvulsants. We had isolated several dihydroxanthone derivatives previously, including oliganthin H, oliganthin I, and oliganthin N, whose structures were similar and delicately elucidated by spectrum analysis or X-ray crystallographic data, from extracts of leaves of Garcinia oligantha. These xanthone analogues were evaluated for anticonvulsant activity, and a novel xanthone, oliganthin H, has been identified as a sound and effective natural inhibitor of convulsions in zebrafish in vivo. A preliminary structure-activity relationship analysis on the relationship between structures of the xanthone analogues and their activities was also conducted. Oliganthin H significantly suppressed convulsant behavior and reduced to about 25% and 50% of PTZ-induced activity, in 12.5 and 25 µM treatment groups (P < 0.01 and 0.001), respectively. Meanwhile, it reduced seizure activity, velocity, seizure duration, and number of bursts in zebrafish larvae (P < 0.05). Pretreatment of oliganthin H significantly restored aberrant induction of gene expressions including npas4a, c-fos, pyya, and bdnf, as well as gabra1, gad1, glsa, and glula, upon PTZ treatment. In addition, in silico analysis revealed the stability of the oliganthin H-GABAA receptor complex and their detailed binding pattern. Therefore, direct interactions with the GABAA receptor and involvement of downstream GABA-glutamate pathways were possible mechanisms of the anticonvulsant action of oliganthin H. Our findings present the anticonvulsant activity of oliganthin H, provide a novel scaffold for further modifications, and highlight the xanthone skeleton as an attractive and reliable resource for the development of emerging AEDs.
Asunto(s)
Anticonvulsivantes/farmacología , Garcinia/química , Xantonas/química , Animales , Anticonvulsivantes/química , Larva/efectos de los fármacos , Estructura Molecular , Pez Cebra/crecimiento & desarrolloRESUMEN
MAIN CONCLUSION: Moringa oleifera TPSs were genome-wide identified for the first time, and a phylogenetic analysis was performed to investigate evolutionary divergence. The qRT-PCR data show that MoTPS genes response to different stress treatments. The trehalose-6-phosphate synthase (TPS) family is involved in a wide range of stress-resistance processes in plants. Its direct product, trehalose-6-phosphate, acts as a specific signal of sucrose status and a regulator to modulate carbon metabolism within the plant. In this study, eight TPS genes were identified and cloned based on the M. oleifera genome; only MoTPS1 exhibited TPS activity among Group I proteins. The characteristics of the MoTPS gene family were determined by analyzing phylogenetic relationships, gene structures, conserved motifs, selective forces, and expression patterns. The Group II MoTPS genes were under relaxed purifying selection or positive selection. The glycosyltransferase family 20 domains generally had lower Ka/Ks ratios and nonsynonymous (Ka) changes compared with those of trehalose-phosphatase domains, which is consistent with stronger purifying selection due to functional constraints in performing TPS enzyme activity. Phylogenetic analyses of TPS proteins from M. oleifera and 17 other plant species indicated that TPS were present before the monocot-dicot split, whereas Group II TPSs were duplicated after the separation of dicots and monocots. Quantitative real-time PCR analysis showed that the expression patterns of TPSs displayed group specificities in M. oleifera. Particularly, Group I MoTPS genes closely relate to reproductive development and Group II MoTPS genes closely relate to high temperature resistance in leaves, stem, stem tip and roots. This work provides a scientific classification of plant TPSs, dissects the internal relationships between their evolution and expressions, and promotes functional researches.
Asunto(s)
Evolución Molecular , Glucosiltransferasas/genética , Moringa oleifera/genética , Proteínas de Plantas/genética , Clonación Molecular , Sequías , Regulación de la Expresión Génica de las Plantas , Prueba de Complementación Genética , Glucosiltransferasas/metabolismo , Filogenia , Proteínas de Plantas/metabolismo , Dominios Proteicos , Salinidad , Temperatura , Levaduras/genéticaRESUMEN
In this study, we examined the anti-Helicobactor pylori effects of the main protoberberine-type alkaloids in Rhizoma Coptidis. Coptisine exerted varying antibacterial and bactericidal effects against three standard H. pylori strains and eleven clinical isolates, including four drug-resistant strains, with minimum inhibitory concentrations ranging from 25 to 50 µg/mL and minimal bactericidal concentrations ranging from 37.5 to 125 µg/mL. Coptisine's anti-H. pylori effects derived from specific inhibition of urease in vivo. In vitro, coptisine inactivated urease in a concentration-dependent manner through slow-binding inhibition and involved binding to the urease active site sulfhydryl group. Coptisine inhibition of H. pylori urease (HPU) was mixed type, while inhibition of jack bean urease was non-competitive. Importantly, coptisine also inhibited HPU by binding to its nickel metallocentre. Besides, coptisine interfered with urease maturation by inhibiting activity of prototypical urease accessory protein UreG and formation of UreG dimers and by promoting dissociation of nickel from UreG dimers. These findings demonstrate that coptisine inhibits urease activity by targeting its active site and inhibiting its maturation, thereby effectively inhibiting H. pylori. Coptisine may thus be an effective anti-H. pylori agent.
Asunto(s)
Antibacterianos/farmacología , Berberina/análogos & derivados , Inhibidores Enzimáticos/farmacología , Helicobacter pylori/efectos de los fármacos , Ureasa/antagonistas & inhibidores , Ureasa/química , Antibacterianos/química , Berberina/química , Berberina/farmacología , Dominio Catalítico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Helicobacter pylori/enzimología , Concentración de Iones de Hidrógeno , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Ureasa/metabolismoRESUMEN
Recent studies demonstrated a significantly increased frequency of epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). The purpose of this study is to investigate the effect of first-line and second-line EGFR-tyrosine kinase inhibitors (TKIs) in the treatment of NSCLC with MPEs harboring exon 19 deletion and L858R mutation. From 2010 to 2015, 203 NSCLC patients with MPEs harboring EGFR mutation treated with EGFR-TKIs were reviewed. The efficacy were evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. The objective response rate (ORR) and disease control rate (DCR) for patients treated with first-line and second-line EGFR-TKIs were 21.9%, 91.4% and 14.7%, 85.3%, respectively. The overall median PFS and OS of enrolled NSCLC patients with MPE were 9.3 months (95% CI, 8.4-10.2 months), 20.9 months (95% CI, 18.9-22.9 months) after first-line TKIs, and 7.6 months (95% CI, 6.6-8.6 months), 15.3 months (95% CI, 13.6-15.9 months) after second-line TKIs. The exon 19 deletion arm had a longer median PFS (9.4 vs 7.1 months, p=0.003) and OS (16.8 vs 13.8 months, p=0.003) compared with the L858R mutation arm after second-line TKIs. In a conclusion, EGFR genotype was an independent predictor of PFS and OS. No significant side effects differences between the two mutation groups was observed for first or second-line EGFR-TKIs. This study demonstrated that EGFR mutations are significant predictors for advanced NSCLC patients with MPE receiving second-line EGFR-TKIs treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Derrame Pleural Maligno/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Derrame Pleural Maligno/complicaciones , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/patología , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM. METHODS: A total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire. RESULTS: The average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable. CONCLUSIONS: Adding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated.
Asunto(s)
Neoplasias Encefálicas/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Irradiación Craneana , Dacarbazina/análogos & derivados , Neoplasias Pulmonares/terapia , Trastornos Neurocognitivos/prevención & control , Calidad de Vida , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia , Dacarbazina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , TemozolomidaRESUMEN
According to the GC-MS analysis, compositional variation was observed between samples of patchouli oil, of which an unknown compound identified as patchoulene epoxide (PAO) was found only in the long-stored oil, whose biological activity still remains unknown. Therefore, the present study aimed to evaluate the potential anti-inflammatory activity with three in vivo inflammatory models: xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. Further investigation into its underlying mechanism on carrageenan-induced paw edema was conducted. Results demonstrated that PAO significantly inhibited the ear edema induced by xylene, lowered vascular permeability induced by acetic acid and decreased the paw edema induced by carrageenan. Moreover, PAO markedly decreased levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO), but increased levels of interleukin-4 (IL-4) and interleukin-10 (IL-10). PAO was also shown to significantly downregulate the protein and mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS). Western blot analysis revealed that PAO remarkably inhibited p50 and p65 translocation from the cytosol to the nucleus by suppressing IKKß and IκBα phosphorylation. In conclusion, PAO exhibited potent anti-inflammatory activity probably by suppressing the activation of iNOS, COX-2 and NF-κB signaling pathways.
Asunto(s)
Compuestos Epoxi/uso terapéutico , Inflamación/tratamiento farmacológico , Aceites de Plantas/química , Pogostemon/química , Animales , Carragenina/toxicidad , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Edema/inducido químicamente , Edema/tratamiento farmacológico , Compuestos Epoxi/química , Femenino , Cromatografía de Gases y Espectrometría de Masas , Inflamación/inducido químicamente , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Pogostone, isolated from Pogostemon cablin, has many biological activities such as potential antibacterial, anticandida, and antifungal. Traditional extraction leads to low output of PO about 17.6 mg/kg from Herba Pogostemonis. The previous literature had reported a synthetic study and the yield had reached 4.48% with strictly controlled reaction conditions. The two methods above cannot meet the large demand of PO; we report a new synthesis method. 4-hydroxy-6-methyl-2-pyrone (1) was added in toluene, with the existence of acylation catalyst 4-dimethylaminopyridine (DMAP), 4-methylvaleric acid (2), and condensing agent dicyclohexylcarbodiimide (DCC), PO was synthesized after the combination of 3-carbon of (1) with 1-OH of (2) in the acylation reaction. The purity had reached 98%, determined by HPLC. The structure was confirmed by spectroscopic methods including infrared, electron ionization mass spectrometry, and nuclear magnetic resonance spectroscopy. PO was totally synthesized in one step including cyclization, with total yield of 27.2%.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Aceites Volátiles/síntesis química , Pogostemon/química , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/química , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cromatografía Líquida de Alta Presión , Ensayos de Selección de Medicamentos Antitumorales , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Aceites Volátiles/química , Pironas/químicaRESUMEN
Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-ß1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Bleomicina/farmacología , Chrysanthemum/química , Extractos Vegetales/farmacología , Animales , Antibióticos Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Bleomicina/efectos adversos , Dióxido de Carbono , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Línea Celular Tumoral , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Fibrosis , Extracción Líquido-Líquido/métodos , Pulmón/metabolismo , Pulmón/patología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Dysfunction of the Na+/K+-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson's disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1 haploinsufficiency (NKAα1+/-) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1+/- mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.
Asunto(s)
Neuronas Dopaminérgicas , Ferroptosis , Mitofagia , Enfermedad de Parkinson , ATPasa Intercambiadora de Sodio-Potasio , Animales , Mitofagia/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Ratones , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Masculino , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Mitocondrias/metabolismo , Mitocondrias/patología , Mitocondrias/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Haploinsuficiencia , Ratones NoqueadosRESUMEN
Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox-induced cardiotoxicity, but whether diminishing these senescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence-associated secretory phenotype (SASP) that affects healthy non-senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl-2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ-H2A.X was used to assess the SASP in the Dox-treated heart. To explore the molecular mechanisms involved, the Bcl-2 inhibitor ABT-199 was employed to eliminate SASP senescent cardiomyocytes. We show that the cardiomyocytes acquire a SASP during Dox treatment. The senescent cardiomyocytes upregulated Bcl-2, although treatment of mice with ABT-199 selectively eliminated SASP senescent cardiomyocytes involved in Dox-induced cardiotoxicity, thus leading to partial alleviation of Dox-induced cardiotoxicity. Moreover, we concluded that SASP factors secreted by senescent cardiomyocytes induced by Dox renders otherwise healthy cardiomyocytes senescent through exosome delivery. Our findings suggest that SASP senescent cardiomyocytes are a significant component of the pathogenesis of Dox-dependent cardiotoxicity and indicate that targeting the clearance of SASP senescent cardiomyocytes could be a new therapeutic approach for Dox-induced cardiac injury.
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Inflammatory response is a crucial factor that affects prognosis and therapeutic effect in tumor cells. Although some studies have shown that inflammation could make DNA more vulnerable to external attacks, resulting in serious DNA damage, the underlying mechanism remains unknown. Then, using tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS), this research elevated the level of inflammation in cancer cells, and hydrogen peroxide (H2O2) and ultraviolet (UV) were utilized as common reactive oxygen species (ROS)-induced DNA damage agents. We show that either H2O2 or UV achieved a more substantial antiproliferative effect in the inflammation environment compared with H2O2 or UV treatment alone. The inflammation environment enhanced H2O2- or UV-induced cell apoptosis and ROS production. Although the phenomenon that inflammation itself could trigger ROS-dependent DNA damage was well known, the underlying mechanism for the sensitization of inflammation to trigger intense DNA damage via ROS in cancer cells remains unclear. In this study, the inflammation-related genes and the corresponding expression information were obtained from the TCGA and fetched genes associated with inflammatory factors. Screening of thirteen inflammatory-related, including ATM, and prognostic genes. In addition, KEGG analysis of prognostic genes shows that biological processes such as DNA replication. ATM and ATR, which belong to the PI3/PI4-kinase family, can activate p53. Inflammation promotes the vulnerability of DNA by activating the ATM/ATR/p53 pathway, while not affecting the DNA damage repair pathway. In brief, this research suggested that inflammation made DNA vulnerable due to the amplifying H2O2- or UV-induced ROS production and the motoring ATM/ATR/p53 pathway. In addition, our findings revealed that inflammation's motoring of the ATM/ATR/p53 pathway plays a crucial role in DNA damage. Therefore, exploring the mechanism between inflammation and ROS-dependent DNA damage would be extremely valuable and innovative. This study would somewhat establish a better understanding of inflammation, DNA damage, and cancer.
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BACKGROUND AND AIMS: Radiotherapy is widely applied for lung adenocarcinoma (LUAD), while individualized differences led to different outcomes. This study aimed to establish a multi-gene risk scoring model to predict the benefits of LUAD patients from radiotherapy, based on different types of cell death respectively. RESULTS: Other than autophagy, pyroptosis, ferroptosis and Immunogenic cell death (ICD), the LUAD prognostic model based on apoptosis had the best performance, and the area under curves (AUCs) of the receiver operating curve (ROC) for 1-, 3-, and 5-year OS were 0.700,0.736,0.723,respectively. Such genes were involved as SLC7A5, EXO1, ABAT, NLRP1 and GAR1. Then patients were divided into high and low risk groups by the median apoptosis-LUAD risk score. For patients in the high-risk group, i.e., the radiotherapy-tolerant group, we screened adjuvant chemotherapy and found that besides the conventional first-line chemotherapy regimen, drugs such as Fludarabine, Pevonedistat, and Podophyllotoxin Bromide may also have potential therapeutic value. CONCLUSION: The multi-gene risk scoring model based on apoptosis might predict the radiotherapy benefits of LUAD patients and for those radioresistant patients classified by the model we also provided effective adjuvant chemicals, which would be used to guide clinical treatment.
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Adenocarcinoma del Pulmón , Apoptosis , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/radioterapia , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/patología , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Tolerancia a Radiación/genética , Muerte CelularRESUMEN
PURPOSE: To investigate the therapeutic effect and underlying mechanism of tetrahydrocurcumin (THC) on nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD). METHODS: NASH rat model was established through long-term feeding HFD, and the steatosis cell model was stimulated via palmitate acid (PA). The therapeutic effect of THC was evaluated in terms of liver function, lipid metabolism, liver pathophysiology, inflammation and oxidative stress in vivo, and lipid accumulation in vitro. The alteration in lipophagy was identified by using western blot and immunofluorescence. mTORC1-TFEB signaling pathway was measured by qRT-PCR, western blot and protein-ligand docking. In addition, chloroquine and MHY1485 were further introduced to validate the effect of THC on lipophagy and mTORC1-TFEB signaling pathway, respectively. RESULTS: THC effectively improved hepatic steatosis, inflammation and oxidative stress in NASH rats, and reduced lipid accumulation in steatosis L02 cells and Hep G2 cells. THC promoted lipophagy with increasing LC3B-II as well as decreasing P62 expression via lysosomal biogenesis upregulation, which was greatly weakened after chloroquine intervention. mTORC1-TFEB is a critical pathway for regulating lysosome in autophagy, THC treatment induced TFEB nucleus translocation via inhibiting mTORC1 to upregulate lysosomal biogenesis. However, these effects were partly eliminated by mTORC1 activator MHY1485. CONCLUSION: THC restored lipophagy to reduce lipid accumulation by regulating mTORC1-TFEB pathway in NASH rats and steatosis hepatocytes. These findings suggested that THC represents a therapeutic candidate for NASH treatment.
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BACKGROUND: The functional relevance of cyclic adenosine monophosphate (cAMP)-response element-binding protein 5 (CREB5) in cancers remains elusive, despite its significance as a member of the CREB family. The current research aims to explore the role of CREB5 in multiple cancers. METHODS: Pan-cancer analysis was performed to explore the expression patterns, prognostic value, mutational landscape as well as single-cell omic, immunologic, and drug sensitivity profiles of CREB5. Furthermore, we incorporated five distinct machine learning algorithms and determined that the least absolute shrinkage and selection operator-COX (LASSO-COX) algorithm, which exhibited the highest C index, was the optimal selection. Subsequently, we constructed a prognostic model centered around CREB5-associated genes. To elucidate the biological function of CREB5 in glioma cells, several assays including cell counting kit-8 (CCK-8), wound healing, transwell, flow cytometric were performed. RESULTS: CREB5 was overexpressed in pan-cancer and was linked to unfavorable prognosis, particularly in glioma. Furthermore, genetic alterations were determined in various types of cancer, and modifications in the CREB5 gene were linked to the prognosis. The single-cell omics and enrichment analyses showed that CREB5 was predominantly expressed in malignant glioma cells and was critically involved in the regulation of various oncogenic processes. Elevated levels of CREB5 were strongly linked with the infiltration of cancer-associated fibroblasts and the Th1 subset of CD4+ T cells. The validated CREB5-associated prognostic model reliably predicted the prognosis and drug response of glioma patients. The in vitro experiments showed that CREB5 promoted glioma cell proliferation, invasion, migration, and gap phase 2/mitotic (G2/M) phase arrest and recruited M2 macrophages into glioma cells. CONCLUSION: CREB5 has the potential to act as an oncogene and a biological marker in multiple cancers, particularly glioma.
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Proteína de Unión al Elemento de Respuesta al AMP Cíclico , Glioma , Multiómica , Humanos , Biomarcadores , Glioma/diagnóstico , Glioma/genética , Inmunoterapia , PronósticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Palmatine is a main bioactive alkaloid of Cortex Phellodendri, which has been commonly prescribed for the treatment of hyperuricemia (HUA) in China. The metabolites of palmatine were crucial to its prominent biological activity. 9-Hydroxy-8-oxypalmatine (9-OPAL) is a novel liver-mediated secondary oxymetabolite of palmatine. AIM OF THE STUDY: The current study was to assess the efficacy of 9-OPAL, a novel liver-mediated secondary oxymetabolite of palmatine derived from Cortex Phellodendri, in experimental HUA mouse model and further explore its underlying mechanism. MATERIALS AND METHODS: An in vitro metabolic experiment with oxypalmatine was carried out using liver samples. We separated and identified a novel liver metabolite, and investigated its anti-HUA effect in mice. HUA mice were induced by potassium oxonate and hypoxanthine daily for one week. After 1 h of modeling, mice were orally administered with different doses of 9-OPAL (5, 10 and 20 mg/kg). The pathological changes of the kidneys were evaluated using hematoxylin-eosin staining (H&E). The acute toxicity of 9-OPAL was assessed. The effects of 9-OPAL on serum levels of uric acid (UA), adenosine deaminase (ADA), xanthine oxidase (XOD), creatinine (CRE), blood urea nitrogen (BUN) and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) or biochemical method. Furthermore, Western blot, quantitative real-time PCR (qRT-PCR) and molecular docking were used to investigate the effect of 9-OPAL on the expression of renal urate transporters and NLRP3 signaling pathway in HUA mice. RESULTS: 9-OPAL had been discovered to be a novel liver-mediated oxymetabolite of palmatine for the first time. Treatment with 9-OPAL significantly reduced the UA, CRE as well as BUN levels, and also effectively attenuated abnormal renal histopathological deterioration with favorable safety profile. Besides, 9-OPAL significantly decreased the serum and hepatic activities of XOD and ADA, dramatically inhibited the up-regulation of UA transporter protein 1 (URAT1) and glucose transporter protein 9 (GLUT9), and reversed the down-regulation of organic anion transporter protein 1 (OAT1). Additionally, 9-OPAL effectively mitigated the renal inflammatory markers (TNF-α, IL-1ß, IL-6 and IL-18), and downregulated the transcriptional and translational expressions of renal Nod-like receptor family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like (ASC) and IL-1ß in HUA mice. Molecular docking results revealed 9-OPAL bound firmly with XOD, OAT1, GLUT9, URAT1, NLRP3, caspase-1, ASC and IL-1ß. CONCLUSIONS: 9-OPAL was found to be a novel liver-mediated secondary metabolite of palmatine with favorable safety profile. 9-OPAL had eminent anti-hyperuricemic and renal-protective effects, and the mechanisms might be intimately associated with repressing XOD activities, modulating renal urate transporter expression and suppressing the NLRP3 inflammasome activation. Our investigation might also provide further experimental evidence for the traditional application of Cortex Phellodendri in the treatment of HUA.
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OBJECTIVE: To investigate the morphological characters of the central nervous system in mature larvae, mature pupae and newly emerged adults of Simulium (Wilhelmia) xingyiense. METHODS: From August to November 2009, the blackfly larvae were collected from the rivulets nearby Niujiao Island in Huaxi of Guiyang City. The mature larvae of S. (Wi.) xingyiense were confirmed based on the diagnostic characteristics of gill spots, postgenal cleft, and rectal gill. The mature pupae were obtained from the rivulets of Da'ao Town and Qingyan Town in Guiyang in March 2011, which were selected according to the characteristics of cocoon and respiratory filaments. Nervous system of the larvae, pupae and newly emerged adults was observed under the light microscope with HE-stained paraffin sections. RESULTS: The central nervous system was composed of brain, subesophageal ganglion and ventral nerve cord. The brain of the larva was divided into two narrowly interconnected egg-shaped lobes. Ventral nerve-cord of the larva consisted of three pairs of thoracic ganglia and eight pairs of abdominal ganglia. The brain of the pupa and adult was composed of protocerebuim, deutocerebrum, and tritocerebrum. The ventral nerve cord of the pupa and adult was similar to that of larva. From outside to inside, the structure characters of the brain and ganglia were similar with nerve sheath, neurocyte and neuropile. The neuropile of protocerebrum contained a pair of mushroom bodies, a central complex and a pair of accessory lobes. The optic lobe was composed of medulla interna, medulla externa and lamina ganglionaris. The deutocerebrum consisted of the antennal lobe and the dorsal lobe. The tritocerebrum connected to the subesophageal ganglion by perioperative esophageal nerve. CONCLUSION: The central nervous system of S. (Wi.) xingyiense is similar to other simuliid blackilies. There is a difference in the number of abdominal ganglion of the mature larva.