Interleukin (IL)–15 is an inflammatory cytokine that constitutes a validated therapeutic target in some immunopathologies, including rheumatoid arthritis (RA). Previously, we identified an IL‐15 antagonist peptide named [K6T]P8, with potential therapeutic application in RA. In the current work, the metabolic stability of this peptide in synovial fluids from RA patients was studied. Moreover, [K6T]P8 peptide was labeled with 99mTc to investigate its stability in human plasma and its biodistribution pattern in healthy rats. The biological activity of [K6T]P8 peptide and its dimer was evaluated in CTLL‐2 cells, using 3 different additives to improve the solubility of these peptides. The half‐life of [K6T]P8 in human synovial fluid was 5.88 ± 1.73 minutes, and the major chemical modifications included peptide dimerization, cysteinylation, and methionine oxidation. Radiolabeling of [K6T]P8 with 99mTc showed a yield of approximately 99.8%. The 99mTc‐labeled peptide was stable in a 30‐fold molar excess of cysteine and in human plasma, displaying a low affinity to plasma proteins. Preliminary biodistribution studies in healthy Wistar rats suggested a slow elimination of the peptide through the renal and hepatic pathways. Although citric acid, sucrose, and Tween 80 enhanced the solubility of [K6T]P8 peptide and its dimer, only the sucrose did not interfere with the in vitro proliferation assay used to assess their biological activity. The results here presented, reinforce nonclinical characterization of the [K6T]P8 peptide, a potential agent for the treatment of RA and other diseases associated with IL‐15 overexpression. 相似文献
Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2-3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs. 相似文献
Many terpenoids are biosynthesized after a cascade of cyclizations and rearrangements of carbocations mediated by terpenoid synthases, as exemplified in th 相似文献
Methanotrophic bacteria play a key role in limiting methane emissions from lakes. It is generally assumed that methanotrophic bacteria are mostly active at the oxic-anoxic transition zone in stratified lakes, where they use oxygen to oxidize methane. Here, we describe a methanotroph of the genera Methylobacter that is performing high-rate (up to 72 μM day−1) methane oxidation in the anoxic hypolimnion of the temperate Lacamas Lake (Washington, USA), stimulated by both nitrate and sulfate addition. Oxic and anoxic incubations both showed active methane oxidation by a Methylobacter species, with anoxic rates being threefold higher. In anoxic incubations, Methylobacter cell numbers increased almost two orders of magnitude within 3 days, suggesting that this specific Methylobacter species is a facultative anaerobe with a rapid response capability. Genomic analysis revealed adaptations to oxygen-limitation as well as pathways for mixed-acid fermentation and H2 production. The denitrification pathway was incomplete, lacking the genes narG/napA and nosZ, allowing only for methane oxidation coupled to nitrite-reduction. Our data suggest that Methylobacter can be an important driver of the conversion of methane in oxygen-limited lake systems and potentially use alternative electron acceptors or fermentation to remain active under oxygen-depleted conditions. 相似文献
While NLRP3‐inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3‐inflammasome protected mice from age‐related increased insulin sensitivity, reduced IGF‐1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the age‐dependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt‐mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age‐associated changes in the heart, preserved cardiac function of aged mice and increased lifespan. 相似文献
Squamous cell carcinoma (SCC) of the tongue is associated with tobacco use, alcohol abuse, and human papillomavirus (HPV) infections. While clinical outcomes have recently improved for HPV‐positive patients in general, 50% of patients suffering from tongue cancer die within 5 years of being diagnosed. Flavonoids are secondary plant metabolites with a wide range of biological activities including antioxidant, anti‐inflammatory, and anticancer activities. Flavonoids have generated high interest as therapeutic agents owing to their low toxicity and their effects on a large variety of cancer cell types. In this literature review, we evaluate the actions of flavonoids on SCC of the tongue demonstrated in both in vivo and in vitro models. 相似文献
Understory fires represent an accelerating threat to Amazonian tropical forests and can, during drought, affect larger areas than deforestation itself. These fires kill trees at rates varying from < 10 to c. 90% depending on fire intensity, forest disturbance history and tree functional traits. Here, we examine variation in bark thickness across the Amazon. Bark can protect trees from fires, but it is often assumed to be consistently thin across tropical forests. Here, we show that investment in bark varies, with thicker bark in dry forests and thinner in wetter forests. We also show that thinner bark translated into higher fire‐driven tree mortality in wetter forests, with between 0.67 and 5.86 gigatonnes CO2 lost in Amazon understory fires between 2001 and 2010. Trait‐enabled global vegetation models that explicitly include variation in bark thickness are likely to improve the predictions of fire effects on carbon cycling in tropical forests. 相似文献
The use of remote sensing tools for mangrove monitoring is currently a strategy used to preserve this important coastal vegetation type. However, the temporal resolution of most satellite imagery limits the analysis of seasonal changes. Here, seasonal trend analysis (STA) was performed using an enhanced vegetation index (EVI) monthly time series (2005–2016) edited from MOD13Q1 products (MODIS Terra), to detect changes in mangrove cover in Sinaloa State in northwestern Mexico. The results were compared with a baseline map derived from a post-classification comparison of two mangrove distribution maps of 2005 and 2015. The STA procedure enabled the identification of mangrove canopy seasonal cycles, with open canopies between May and July and closed canopies from August to October. It was also possible to detect annual and long-term changes in canopy, with positive trends observed in most of Sinaloa’s mangrove ecosystems, which partially agree with the post-classification comparison results. Despite their coarse resolution, using the MODIS EVI products proved to be useful to confidently detect short- and long-term changes in mangrove cover, particularly in large ecosystems. Consequently, land use change analyses using these inputs could help to take actions related to mangrove cover management, considering the trends of change in this vegetation type.