RESUMO
A novel glucoside bletilloside A (1) was isolated from the tubers of Bletilla striata, together with seven known compounds (2-8). Their structures were determined on the basis of extensive spectroscopic analyses. All compounds were evaluated for the inhibition on NO production effects in RAW 264.7 macrophage cells, while militarine (4) and dactylorhin A (5) exhibited moderate inhibitory effects.
Assuntos
Bibenzilas/isolamento & purificação , Bibenzilas/farmacologia , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Orchidaceae/química , Animais , Bibenzilas/química , Glucosídeos/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Tubérculos/químicaRESUMO
BACKGROUND: NUDT21 (Nudix Hydrolase 21) has been shown to play an essential role in multiple biological processes. Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world. However, the biological function of NUDT21 in PAAD remains rarely understood. The aim of this research was to identify the prediction value of NUDT21 in diagnosis, prognosis, immune infiltration, and signal pathway in PAAD. METHODS: Combined with the data in online databases, we analyzed the expression, immune infiltration, function enrichment, signal pathway, diagnosis, and prognosis of NUDT21 in PAAD. Then, the biological function of NUDT21 and its interacted protein in PAAD was identified through plasmid transduction system and protein mass spectrometry. Expression of NUDT21 was further verified in clinical specimens by immunofluorescence. RESULTS: We found that NUDT21 was upregulated in PAAD tissues and was significantly associated with the diagnosis and prognosis of pancreatic cancer through bioinformatic data analysis. We also found that overexpression of NUDT21 enhanced PAAD cells proliferation and migration, whereas knockdown NUDT21 restored the effects through in vitro experiment. Moreover, NDUFS2 was recognized as a potential target of NUDT21.We further verified that the expression of NDUFS2 was positively correlated with NUDT21 in PAAD clinical specimens. Mechanically, we found that NUDT21 stabilizes NDUFS2 and activates the PI3K-AKT signaling pathway. CONCLUSION: Our investigation reveals that NUDT21 is a previously unrecognized oncogenic factor in the diagnosis, prognosis, and treatment target of PAAD, and we suggest that NUDT21 might be a novel therapeutic target in PAAD.
Assuntos
Adenocarcinoma , Fator de Especificidade de Clivagem e Poliadenilação , NADH Desidrogenase , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/genética , Proliferação de Células , NADH Desidrogenase/genética , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fator de Especificidade de Clivagem e Poliadenilação/genéticaRESUMO
Sinojackia Hu represents the first woody genus described by Chinese botanists, with all species classified as endangered ornamental plants endemic to China. Their characteristic spindle-shaped fruits confer high ornamental value to the plants, making them favored in gardens and parks. Nevertheless, the fruits likely pose a germination obstacle, contributing to the endangered status of this lineage. Here we report the chromosome-scale genome of S. xylocarpa, and explore the mechanisms underlying its endangered status, as well as its population dynamics throughout evolution. Population genomic analysis has indicated that S. xylocarpa experienced a bottleneck effect following the recent glacial period, leading to a continuous population reduction. Examination of the pericarp composition across six stages of fruit development revealed a consistent increase in the accumulation of lignin and fiber content, responsible for the sturdiness of mature fruits' pericarps. At molecular level, enhanced gene expression in the biosynthesis of lignin, cellulose and hemicellulose was detected in pericarps. Therefore, we conclude that the highly lignified and fibrotic pericarps of S. xylocarpa, which inhibit its seed germination, should be its threatening mechanism, thus proposing corresponding strategies for improved conservation and restoration. This study serves as a seminal contribution to conservation biology, offering valuable insights for the study of other endangered ornamental plants.
RESUMO
Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.
RESUMO
Pancreatic ductal adenocarcinoma is a highly malignant cancer with poor prognosis, for which effective therapeutic strategies are urgently needed. The dual-specificity phosphatase PTPMT1 is localized in mitochondria and highly expressed in various cancers. Here, we investigated the function of PTPMT1 in pancreatic ductal adenocarcinoma. We inhibited its expression in pancreatic cancer cell lines using siRNAs or the specific PTPMT1 inhibitor alexidine dihydrochloride and observed that PTPMT1 silencing in pancreatic cancer cell lines drastically reduced cell viability, caused mitochondrial damage, and impaired mitochondrial function. Co-immunoprecipitation analysis demonstrated that PTPMT1 could interact with SLC25A6 and NDUFS2, indicating that it may modulate mitochondrial function via the SLC25A6-NDUFS2 axis. Collecively, our data highlight PTPMT1 as an important factor in pancreatic ductal adenocarcinoma and a potential therapeutic target.
RESUMO
A polysaccharide, isolated and purified from the aqueous extract of nettle plant Urtica fissa, was found to consist of D-glucose and D-arabinose. Molecular weight was determined to be Mn 4140. The NMR experiments (¹H, ¹³C, ¹H--¹H COSY, TOCSY, HSQC, NOESY, and HMBC) revealed the structure as the following repeating unit: -->6)-α-D-Glcp-(1-->6)-α-D-Glcp-(1-->6)-ß-D-Glcp--(1-->5)-ß-D-Araf-(1-->3)-ß-D-Glcp-(1-->
Assuntos
Medicamentos de Ervas Chinesas/isolamento & purificação , Ressonância Magnética Nuclear Biomolecular/métodos , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Urticaceae/química , Sequência de Carboidratos , Medicamentos de Ervas Chinesas/química , Raízes de Plantas/químicaRESUMO
BACKGROUND: N-Methyl-d-aspartate receptor (NMDAR) in the hypothalamic paraventricular nucleus (PVN) plays critical roles in regulating sympathetic outflow. Studies showed that acute application of the antagonists of NMDAR or its subunits would reduce sympathetic nerve discharges. However, little is known about the effect of long-term management of NMDAR in hypertensive animals. METHODS: PEAQX, the specific antagonist of NMDAR subunit 2A (GluN2A) was injected into both sides of the PVN of two-kidney, one-clip (2K1C) renal hypertensive rats and control (normotensive rats) for 3 weeks. RESULTS: Three weeks of PEAQX infusion significantly reduced the blood pressure of the 2K1C rats. It managed to resume the balance between excitatory and inhibitory neural transmitters, reduce the level of proinflammatory cytokines and reactive oxygen species in the PVN, and reduce the level of norepinephrine in plasma of the 2K1C rats. PEAQX administration also largely reduced the transcription and translation levels of GluN2A and changed the expression levels of NMDAR subunits 1 and 2B (GluN1 and GluN2B). In addition, NMDAR was known to function through activating the extracellular regulated protein kinases (ERK) or phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways. In our study, we found that in the PVN of 2K1C rats treated with PEAQX, the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), ERK1/2, and cAMP-response element-binding protein (CREB) significantly reduced, while the phosphorylation level of PI3K did not change significantly. CONCLUSIONS: Chronic blockade of GluN2A alleviates hypertension through suppression of MEK/ERK/CREB pathway.
Assuntos
Hipertensão , Núcleo Hipotalâmico Paraventricular , Receptores de N-Metil-D-Aspartato , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipertensão/prevenção & controle , Sistema de Sinalização das MAP Quinases , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Three polysaccharides were isolated from the roots of Urtica fissa by extraction, ultrafiltration, anion-exchange, and gel-filtration chromatography. The structures were characterized using acetylation, methylation, and spectral methods (GCMS, NMR). All three polysaccharides are mainly composed of D-arabinofuranosyl, D-galactopyranosyl, D-glucopyranosyl residues with different structural characteristics. Polysaccharide A of MW 5.2 x 10(3) contained a linear chain of 1-linked beta-D-glucopyranosyl, 1,6-linked beta-D-glucopyranosyl, 1,6-linked alpha-galactopyranosyl, and 1,5-linked beta-arabinofuranosyl moieties. Polysaccharide B of MW 7.7 x 10(4) possessed a chain consisting of 1,5-linked alpha-D-arabinofuranosyl, 1,3-linked beta-D-mannopyranosyl, 1,6-linked beta-D-glucopyranosyl, and 1,6-linked alpha-D-galactopyranosyl residues, but 4-O of alpha-D-galactopyranosyl residues were branched by terminal beta-D-glucopyranosyl residues. Polysaccharide C of MW 5.3 x 10(4) composed of a chain of 1,5-linked alpha-D-arabinofuranosyl, 1,4-linked beta-D-galactopyranosyl, 1,5-linked beta-D-xylopyranosyl, 1,4-linked beta-D-mannopyranosyl, 1-linked beta-D-glucopyranosyl residues, and the terminal beta-D-glucopyranosyl residues are attached to 3-O positions of 1,6-linked alpha-D-glucopyranosyl residues.
Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Urticaceae/química , Cromatografia Gasosa-Espectrometria de Massas , Ressonância Magnética Nuclear Biomolecular , Raízes de Plantas/químicaRESUMO
The microbiological transformation of epothilone A (1) by Aspergillus niger AS 3.739 afforded four main metabolites. Their structures were elucidated by (1)H, (13)C NMR and HSQC, COSY, HMBC, and NOESY spectra as trans-12,13-hydroxylated epothilone A (2), cis-12,13-hydroxylated epothilone A (3), trans-12,15-epoxidated epothilone A (4), and cis-12,15-epoxidated epothilone A (5). All four compounds were firstly found based on their stereochemistry. These new compounds displayed cytotoxicity against human breast carcinoma cells MCF-7 with IC(50) 9.88 microg/ml of 2, 2.52 microg/ml of 3, 9.88 microg/ml of 4, and 5.68 microg/ml of 5.
Assuntos
Antineoplásicos Fitogênicos/metabolismo , Aspergillus niger/metabolismo , Biotransformação , Epotilonas/metabolismo , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Epotilonas/química , Feminino , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , EstereoisomerismoRESUMO
Tau protein, a microtubule-associated protein, has a high specific expression in neurons and axons. Because traumatic spinal cord injury mainly affects neurons and axons, we speculated that tau protein may be a promising biomarker to reflect the degree of spinal cord injury and prognosis of motor function. In this study, 160 female Sprague-Dawley rats were randomly divided into a sham group, and mild, moderate, and severe spinal cord injury groups. A laminectomy was performed at the T8 level to expose the spinal cord in all groups. A contusion lesion was made with the NYU-MASCIS impactor by dropping a 10 g rod from heights of 12.5 mm (mild), 25 mm (moderate) and 50 mm (severe) upon the exposed dorsal surface of the spinal cord. Tau protein levels were measured in serum and cerebrospinal fluid samples at 1, 6, 12, 24 hours, 3, 7, 14 and 28 days after operation. Locomotor function of all rats was assessed using the Basso, Beattie and Bresnahan locomotor rating scale. Tau protein concentration in the three spinal cord injury groups (both in serum and cerebrospinal fluid) rapidly increased and peaked at 12 hours after spinal cord injury. Statistically significant positive linear correlations were found between tau protein level and spinal cord injury severity in the three spinal cord injury groups, and between the tau protein level and Basso, Beattie, and Bresnahan locomotor rating scale scores. The tau protein level at 12 hours in the three spinal cord injury groups was negatively correlated with Basso, Beattie, and Bresnahan locomotor rating scale scores at 28 days (serum: r = -0.94; cerebrospinal fluid: r = -0.95). Our data suggest that tau protein levels in serum and cerebrospinal fluid might be a promising biomarker for predicting the severity and functional outcome of traumatic spinal cord injury.