Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor ...family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3(-/-) mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1-mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.
The challenges and difficulties associated with conventional drug delivery systems have led to the emergence of novel, advanced targeted drug delivery systems. Therapeutic drug delivery of proteins ...and peptides to the lungs is complicated owing to the large size and polar characteristics of the latter. Nevertheless, the pulmonary route has attracted great interest today among formulation scientists, as it has evolved into one of the important targeted drug delivery platforms for the delivery of peptides, and related compounds effectively to the lungs, primarily for the management and treatment of chronic lung diseases. In this review, we have discussed and summarized the current scenario and recent developments in targeted delivery of proteins and peptide-based drugs to the lungs. Moreover, we have also highlighted the advantages of pulmonary drug delivery over conventional drug delivery approaches for peptide-based drugs, in terms of efficacy, retention time and other important pharmacokinetic parameters. The review also highlights the future perspectives and the impact of targeted drug delivery on peptide-based drugs in the coming decade.
•Prominence of pulmonary drug delivery over the other modes of administration.•Pulmonary delivery of Protein/peptide-based biologics for optimal pharmacokinetics.•Translational efficacy of protein/peptide-based therapeutics for clinical advancement.•Drug conjugated protein/peptide biologics to restore an optimal respiratory health.
Obesity is associated with inflammation that can drive metabolic defects such as hyperlipidemia and insulin resistance. Specific metabolites can contribute to inflammation, but nutrient intake and ...obesity are also associated with altered bacterial load in metabolic tissues (i.e. metabolic endotoxemia). These bacterial cues can contribute to obesity-induced inflammation. The specific bacterial components and host receptors that underpin altered metabolic responses are emerging. We previously showed that Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) activation with bacterial peptidoglycan (PGN) caused insulin resistance in mice. We now show that PGN induces cell-autonomous lipolysis in adipocytes via NOD1. Specific bacterial PGN motifs stimulated lipolysis in white adipose tissue (WAT) explants from WT, but not NOD1⁻/⁻mice. NOD1-activating PGN stimulated mitogen activated protein kinases (MAPK),protein kinase A (PKA), and NF-κB in 3T3-L1 adipocytes. The NOD1-mediated lipolysis response was partially reduced by inhibition of ERK1/2 or PKA alone, but not c-Jun N-terminal kinase (JNK). NOD1-stimulated lipolysis was partially dependent on NF-κB and was completely suppressed by inhibiting ERK1/2 and PKA simultaneously or hormone sensitive lipase (HSL). Our results demonstrate that bacterial PGN stimulates lipolysis in adipocytes by engaging a stress kinase, PKA, NF-κB-dependent lipolytic program. Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Treating fracture nonunion with endothelial progenitor cells (EPCs) is a promising approach. Nevertheless, the effect of different EPC-related cell populations remains unclear. In this study, ...we compared the therapeutic potential of early (E-EPCs) and late EPCs (L-EPCs).
Methods
Male Fischer 344 rats were used for cell isolation and in vivo experiments. Bone marrow-derived E-EPCs and L-EPCs were kept in culture for seven to ten days and four weeks, respectively. For each treatment group, we seeded one million cells on a gelatin scaffold before implantation in a segmental defect created in a rat femur; control animals received a cell-free scaffold. Bone healing was monitored via radiographs for up to ten weeks after surgery. In vitro, secretion of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 was quantified by ELISA for both cell populations. Tube formation assays were also performed.
Results
Final radiographs showed complete (four out of five rats) or partial (one out of five rats) union with E-EPC treatment. In contrast, complete healing was achieved in only one of five animals after L-EPC implantation, while control treatment resulted in nonunion in all animals. In vitro, E-EPCs released more VEGF, but less BMP-2 than L-EPCs. In addition, L-EPCs formed longer and more mature tubules on basement membrane matrix than E-EPCs. However, co-culture with primary osteoblasts stimulated tubulogenesis of E-EPCs while inhibiting that of L-EPCs.
Conclusions
We demonstrated that bone marrow-derived E-EPCs are a better alternative than L-EPCs for treatment of nonunion. We hypothesize that the expression profile of E-EPCs and their adaptation to the local environment contribute to superior bone healing.
Many recent developments on generative models for natural images have relied on heuristically-motivated metrics that can be easily gamed by memorizing a small sample from the true distribution or ...training a model directly to improve the metric. In this work, we critically evaluate the gameability of these metrics by designing and deploying a generative modeling competition. Our competition received over 11000 submitted models. The competitiveness between participants allowed us to investigate both intentional and unintentional memorization in generative modeling. To detect intentional memorization, we propose the "Memorization-Informed Frechet Inception Distance" (MiFID) as a new memorization-aware metric and design benchmark procedures to ensure that winning submissions made genuine improvements in perceptual quality. Furthermore, we manually inspect the code for the 1000 top-performing models to understand and label different forms of memorization. Our analysis reveals that unintentional memorization is a serious and common issue in popular generative models. The generated images and our memorization labels of those models as well as code to compute MiFID are released to facilitate future studies on benchmarking generative models.
Compulsive buying (CB) is a behavioral addiction that is conceptualized as an obsessive–compulsive and impulsive–control disorder. The Richmond Compulsive Buying Scale (RCBS), a six-item ...self-reporting instrument that has been validated worldwide, was developed based on this theoretical background. This study aimed to adapt RCBS to the Chinese population (RCBS-TC) to guide future national and international prevalence studies. Methods. This methodological study was conducted in two phases. Phase 1 involved the forward and backward translation of RCBS, the content and face validation of the RCBS, and the evaluation of its translation adequacy. Phase 2 involved the psychometric testing of RCBS-TC for its internal consistency, stability, and construct validity using confirmatory factor analysis (CFA). Results. In Phase 1, RCBS-TC obtained satisfactory item-level (I-CVI = 83.3%–100%) and scale-level content validity index (CVI/AVE = 97.2%), comprehensibility (100%), and translation adequacy intraclass correlation coefficient (ICC) = 0.858. In Phase 2, based on data collected from 821 adults, RCBS-TC demonstrated a satisfactory internal consistency (Cronbach’s α = .88; corrected item-total correlation coefficients = 0.61–0.78) 2-week test–retest reliability (ICC = 0.82 based on 61 university students). For construct validation, the CFA results indicated that the corrected first-order two-factor models were acceptable with the same goodness-of-fit indices (χ2/df = 8.56, CFI = 0.99, NFI = 0.98, IFI = 0.99, and RMSEA = 0.09). The 2-week test–retest reliability of RCBS-TC (n = 61) was also satisfactory (ICC = 0.82). Discussion and conclusions. This methodological study adopted appropriate and stringent procedures to ensure that the translation and validation of RCBS-TC was of quality. The results indicate that this scale has a satisfactory reliability and validity for the Chinese population.
Since 1996, the Center for Education Reform has released an annual report card, grading each state’s charter school legislation and labeling as the “strongest” those laws placing the fewest and ...slightest restrictions on charter schools. While the Center for Education Reform rankings have undoubtedly been the most influential, at least four other systems have been developed. In this article, we analyze the different ranking systems, including a new approach we have developed in order to illustrate the arbitrariness of any given ranking system and to highlight some key charter school issues. We then investigate the general, popular phenomenon of rankings in the field of education, exploring the benefits, drawbacks, and appeal of such rankings.
Obesity associates with inflammation, insulin resistance, and higher blood lipids. It is unclear if immune responses facilitate lipid breakdown and release from adipocytes via lipolysis in a separate ...way from hormones or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis from adrenergic or hormonal stimuli. Our data show that inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. IRE1-mediated lipolysis was specific for inflammatory triggers since IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. Inhibiting IRE1 kinase activity blocked NF-κB activation, interleukin-6 secretion, and adipocyte-autonomous lipolysis from inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signaling in adipocytes, suggesting that inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. We found no role for canonical unfolded protein responses or ABL kinases in linking ER stress to IRE1-mediated lipolysis. Adiponectin-Cre-mediated IRE1 knockout in mice showed that adipocyte IRE1 was required for inflammatory ligand-induced lipolysis in adipose tissue explants and that adipocyte IRE1 was required for approximately half of the increase in blood triglycerides after a bacterial endotoxin-mediated inflammatory stimulus in vivo. Together, our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders.
Objective
Obesity is characterized by inflammation that can impair endocrine control of cell metabolism. The triggers and stress responses of these immune‐mediated defects are ill‐defined. There is a ...reciprocal relationship between inflammation and lipolysis in adipocytes, but hormones and adrenergic signals can also stimulate lipolytic programs in adipocytes. This study aimed to identify the cell stress responses that differentiate inflammatory and hormonal triggers of lipolysis in adipocytes.
Methods
Lipolysis was measured by glycerol release from 3T3‐L1 adipocytes treated with inhibitors of ER stress, inositol‐requiring protein 1α (IRE1α) or tyrosine kinases before stimulation with inflammatory lypolytic stimuli. The inflammatory stimuli included bacterial peptidoglycan, lipopolysaccharide, and tumor necrosis factor. The Hormonal or adrenergic stimuli tested included isoproterenol and forskolin. Inflammation was characterized by Il6 secretion and NF‐κβ activity.
Results
Inhibition of the kinase activity of IRE1α was sufficient to block lipolysis and Il6 secretion caused by thapsigargin‐induced ER‐stress in adipocytes. Inhibition of IRE1α kinase activity blocked augmented lipolysis from inflammatory, but not hormonal stimuli. Inhibition of IRE1α also blocked augmented Il6 secretion from all inflammatory stimuli. Inhibition of IRE1α blocked the increased NF‐κB activity from all inflammatory stimuli except for lipopolysaccharide. Inhibition of ABL kinases with imatinib did not alter lipolysis. Inhibition of IRE1α RNase activity did not alter lipolysis. The potent RIPK2 inhibitor ponatinib blocked lipolysis, Il6 secretion, and NF‐κβ activation stimulated by peptidoglycan, but did not alter lipolysis from other inflammatory stimuli, despite attenuated Il6 secretion.
Conclusions
The ER stress sensor IRE1α is essential for inflammation‐induced lipolysis and Il6 secretion in adipocytes. Neither RIPK2 nor NF‐κβ can fully capture the IRE1α lipolyitic pathway from inflammatory stimuli. These findings show that IRE1α discriminates inflammation‐induced lipolysis linked to ER stress from hormonal or adrenergic triggers of adipocyte lipolysis.
Support or Funding Information
This research is supported by operating grants to JDS from the Natural Sciences and Engineering Research Council (NSERC). JDS held CDA Scholar (SC‐5‐12‐3891‐JS) and CIHR New Investigator awards (MSH‐136665) and holds a Canada Research Chair in Metabolic Inflammation. BD was supported by an Ontario Graduate Scholarship (OGS). KF is supported by an NSERC postdoctoral fellowship.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Educational policy controversies in the United States invariably implicate legal issues. Policy debates about testing and school choice, for example, cannot be disentangled from legal rights and ...mandates. The same is true for issues such as funding, campus safety, speech and religion rights, as well as the teaching of immigrant students. Written for a general audience, this new twelve-chapter book explores these compelling educational policy issues through that legal lens, building an understanding of both law and policy. (DIPF/Orig.).
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