Asymmetric Biomimetic Transamination of Trifluoromethyl Ketones.

In the presence of chiral pyridoxamine 4b as the catalyst and 2,2-diphenylglycine (3) as the amine source, asymmetric biomimetic transamination of trifluoromethyl ketones produces optically active α-trifluoromethyl amines 6 in 81-98% yields with 88-95% ee's under mild conditions.

The link between exposure to violent media, normative beliefs about aggression, self-control, and aggression: A comparison of traditional and cyberbullying.

Adolescence is a high-risk age for exposure to violent media (EVM) and bullying. Some previous theories and empirical studies have highlighted a moderated mediating model that normative beliefs about aggression (NBA) as a mediator and self-control (SC) as a moderator for the link between EVM and aggressive behaviors (including bullying behaviors). However, most previous studies analyzed traditional bullying (TB) and cyberbullying (CB) separately, which is not conducive to finding the differences between the two bullying behaviors. Therefore, this study aims to compare the differences between risk prediction models of TB and CB among adolescents. A total of 777 Chinese adolescent students (336 girls; Mage = 13.57 ± 0.98) completed questionnaires including EVM, NBA, TB, CB, and SC. The results showed that: (1) EVM was positively related to adolescent TB/CB; (2) NBA mediated the above relations; and (3) SC buffers the direct effect of EVM on TB and the effect of NBA on TB. However, SC buffers the effect of NBA on adolescent CB but not buffers the direct effect of EVM on CB. This study highlights the necessity of distinguishing offline and online situations in aggressive behavior research. We suggested "online disinhibit hypothesis" would be adopted to explain why protector factors (e.g., SC) do not buffer the link between aggression-related risk factors (e.g., EVM) and online aggression (e.g., CB).

A Lanthanide Upconversion Nanothermometer for Precise Temperature Mapping on Immune Cell Membrane.

Cell temperature monitoring is of great importance to uncover temperature-dependent intracellular events and regulate cellular functions. However, it remains a great challenge to precisely probe the localized temperature status in living cells. Herein, we report a strategy for in situ temperature mapping on an immune cell membrane for the first time, which was achieved by using the lanthanide-doped upconversion nanoparticles. The nanothermometer was designed to label the cell membrane by combining metabolic labeling and click chemistry and can leverage ratiometric upconversion luminescence signals to in situ sensitively monitor temperature variation (1.4% K-1). Moreover, a purpose-built upconversion hyperspectral microscope was utilized to synchronously map temperature changes on T cell membrane and visualize intracellular Ca2+ influx. This strategy was able to identify a suitable temperature status for facilitating thermally stimulated calcium influx in T cells, thus enabling high-efficiency activation of immune cells. Such findings might advance understandings on thermally dependent biological processes and their regulation methodology.

Oligonucleotide Discrimination Enabled by Tannic Acid-Coordinated Film-Coated Solid-State Nanopores.

Discrimination of nucleotides serves as the basis for DNA sequencing using solid-state nanopores. However, the translocation of DNA is usually too fast to be detected, not to mention nucleotide discrimination. Here, we utilized polyphenolic TA and Fe3+, an attractive metal-organic thin film, and achieved a fast and robust surface coating for silicon nitride nanopores. The hydrophilic coating layer can greatly reduce the low-frequency noise of an original unstable nanopore, and the nanopore size can be finely tuned in situ at the nanoscale by simply adjusting the relative ratio of Fe3+ and TA monomers. Moreover, the hydrogen bonding interaction formed between the hydroxyl groups provided by TA and the phosphate groups of DNAs significantly increases the residence time of a short double-strand (100 bp) DNA. More importantly, we take advantage of the different strengths of hydrogen bonding interactions between the hydroxyl groups provided by TA and the analytes to discriminate between two oligonucleotide samples (oligodeoxycytidine and oligodeoxyadenosine) with similar sizes and lengths, of which the current signal patterns are significantly different using the coated nanopore. The results shed light on expanding the biochemical functionality of surface coatings on solid-state nanopores for future biomedical applications.

Stress-Busting Program for Family Caregivers: Validation of the Spanish version using biomarkers and quality-of-life measures.

Hispanic family caregivers of people with dementia experience higher levels of stress compared to non-Hispanic white caregivers. Long-term stress causes depression, caregiver burden, cellular aging, and dysregulation of the immune, nervous, and endocrine systems. The purpose of this study was to determine the validity of the Spanish version of the English Stress-Busting Program (SBP) for Family Caregivers by determining changes in quality-of-life measures and biomarkers. Thirty-six caregivers completed the SBP in the language of their choice (14 Spanish-speaking Hispanics [HS], 8 English-speaking Hispanics [HE], and 14 non-Hispanic English [NHE] speakers). Quality-of-life measures included the Perceived Stress Scale, the Screen for Caregiver Burden, and the Center for Epidemiologic Studies Depression Scale. Assessment of oral health and immunity included salivary flow rate, pH, buffer capacity, total protein, and secretory immunoglobulin A (sIgA). Indicators of stress (salivary cortisol), inflammation (C-reactive protein), and cellular aging (leukocyte telomere length) were assessed. Following completion of the SBP, the Spanish-speaking group had less depression and caregiver burden along with improved oral health and reduced cellular aging. When comparing baseline values to post-intervention, all three groups showed significant improvement in subjective caregiver burden. When the data from all three groups were combined, biomarkers that showed improvement after nine weeks of SBP included the stress hormone cortisol, salivary pH, and leukocyte telomere length. The results indicate that the Spanish SBP reduces caregiver stress as assessed by quality-of-life indicators and biomarkers. The Spanish SBP can help to mitigate health disparities in Hispanic Spanish-speaking caregivers.

Persistence, effectiveness and safety of dabigatran in "real-world" Chinese patients with nonvalvular atrial fibrillation.

The purpose of this study is to provide detailed data on treatment persistence and clinical outcomes in Chinese patients with nonvalvular atrial fibrillation (NVAF). A single-center retrospective observational study was conducted. A total of 26,663 NVAF patients were enrolled from January 1, 2014 to December 31, 2017, clinical information of whom were from inpatient and outpatients data system was collected. The 1-year treatment persistence rates of 11,350 dabigatran users were 24.5% in 2014, 36.6% in 2015, 37.7% in 2016 and 51.8% in 2017. The predominant reason of non-persistence patients was the cost of treatment. Incidence rates of all-cause death, ischemic stroke and embolism were 1.99/100 person-years, 2.56/100 person-years and 0.77/100 person-years, respectively. Incidence rates of minor bleeding events, intracranial hemorrhage and gastrointestinal hemorrhage were 10.05/100 person-years, 0.51/100 person-years and 0.85/100 person-years, respectively. In conclusion, it is of importance for Chinese clinicians to know about these information because dabigatran is a relatively new drug in China. Compared with other reported data, patients of this study have (1) lower dabigatran persistence and lower incident rates of all-cause death, systemic embolism, minor bleeding events and gastrointestinal hemorrhage and (2) higher incident rates of ischemic stroke and intracranial hemorrhage.

The Nuclear Localization of the DnaJ-Like Zinc Finger Domain-Containing Protein EDA3 Affects Seed Development in Arabidopsis thaliana.

The DnaJ-like zinc finger domain-containing proteins are involved in different aspects of plastid function and development. Some of these proteins were recently reported to have dual subcellular localization in the nucleus and plastids. One member of this family, PSA2 (AT2G34860), was found to localize to the thylakoid lumen and regulate the assembly of photosystem I (PSI). However, PSA2 was also annotated as Embryo sac Development Arrest 3 (EDA3) from the observation that its embryo sac development was arrested at the two-nuclear stage. In this study, we characterized the eda3 mutant, and demonstrated that, as compared with the wild-type (WT) plants, the mutant has shorter siliques, fewer siliques per plant, and fewer seeds per silique. Both aborted and undeveloped ovules were observed in siliques of the mutant. By immunoblot analysis, we found that, different from the chloroplast localization in mature leaves, EDA3 localizes in the nucleus in seeds. A nuclear localization signal was identified from the deduced amino acid sequence of EDA3, and also proved to be sufficient for directing its fusion peptide into the nucleus.

Mammalian Target of Rapamycin at the Crossroad Between Alzheimer's Disease and Diabetes.

Accumulating evidence suggests that Alzheimer's disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer's disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer's disease (Haaksma et al, PLoS One 12(5):e0177044, 2017). Type 2 diabetes mellitus is especially notable as the disease shares many overlapping pathologies observed in patients with Alzheimer's disease, including hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia, inflammation, and cognitive dysfunction, as described in Chap. 8 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al, Neurology 53(9):1937-1942, 1999; Voisin et al, Rev Med Interne 24(Suppl 3):288s-291s, 2003; Janson et al. Diabetes 53(2):474-481, 2004; Ristow M, J Mol Med (Berl) 82(8):510-529, 2004; Whitmer et al, BMJ 330(7504):1360, 2005, Curr Alzheimer Res 4(2):103-109, 2007; Ohara et al, Neurology 77(12):1126-1134, 2011). Although nondiabetic older adults also experience age-related cognitive decline, diabetes is uniquely associated with a twofold increased risk of Alzheimer's disease, as described in Chap. 2 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al. Neurology 53(9):1937-1942, 1999; Ohara et al, Neurology 77(12):1126-1134, 2011). Good glycemic control has been shown to improve cognitive status (Cukierman-et al, Diabetes Care 32(2):221-226, 2009), and the use of insulin sensitizers is correlated with a lower rate of cognitive decline in older adults (Morris JK, Burns JM, Curr Neurol Neurosci Rep 12(5):520-527, 2012). At the molecular level, the mechanistic/mammalian target of rapamycin (mTOR) plays a key role in maintaining energy homeostasis. Nutrient availability and cellular stress information, both extracellular and intracellular, are integrated and transduced through mTOR signaling pathways. Aberrant regulation of mTOR occurs in the brains of patients with Alzheimer's disease and in numerous tissues of individuals with type 2 diabetes (Mannaa et al, J Mol Med (Berl) 91(10):1167-1175, 2013). Moreover, modulating mTOR activity with a pharmacological inhibitor, rapamycin, provides wide-ranging health benefits, including healthy life span extension in numerous model organisms (Vellai et al, Nature 426(6967):620, 2003; Jia et al, Development 131(16):3897-3906, 2004; Kapahi et al, Curr Biol 14(10):885-890, 2004; Kaeberlein et al, Science 310(5751):1193-1196, 2005; Powers et al, Genes Dev 20(2):174-184, 2006; Harrison et al, Nature 460(7253):392-395, 2009; Selman et al, Science 326(5949):140-144, 2009; Sharp ZD, Strong R, J Gerontol A Biol Sci Med Sci 65(6):580-589, 2010), which underscores its importance to overall organismal health and longevity. In this chapter, we discuss the physiological role of mTOR signaling and the consequences of mTOR dysregulation in the brain and peripheral tissues, with emphasis on its relevance to the development of Alzheimer's disease and link to type 2 diabetes.

Autofluorescence-Free Immunoassay Using X-ray Scintillating Nanotags.

Autofluorescence background in complex biological samples is a major challenge in achieving high sensitivity of fluorescence immunoassays (FIA). Here we report an X-ray luminescence-based immunoassay for high-sensitivity detection of biomarkers using X-ray scintillating nanotags. Due to the weak scattering and absorption of most biological chromophores by X-ray excitation, a low-dose X-ray source can be used to produce intense scintillating luminescence from the nanotags for autofluorescence-free biosensing. To demonstrate this concept, we designed and synthesized NaGdF4:Tb@NaYF4 core/shell nanoparticles as kind of high-efficiency X-ray scintillating nanotags, which are able to convert high-energy X-ray photons to visible light without autofluorescence in biological samples. Notably, strong X-ray absorption and minimized surface quenching arising from the heavy Gd3+/Tb3+ atoms and core/shell architecture of the nanoparticles were found to be critically important for high-efficiency X-ray excited luminescence for high-sensitivity biosensing. Our method allows for sensing alpha-fetoprotein (AFP) biomarkers with a detection limit down to 0.25 ng/mL. Moreover, the as-described X-ray luminescence immunoassay exhibited an excellent biological specificity, high stability, and sample recovery, implying an opportunity for applications in complex biological samples. Consequently, our method can be readily extended for multiplexing sensing and medical diagnosis.

Cybervictimization and Non-Suicidal Self-Injury Among Chinese College Students: an Exploration Through the Lens of Experiential Avoidance Model.

Purpose: Non-suicidal self-injury (NSSI) is a growing public health concern among college students, with cybervictimization (CV) emerging as a significant contributing factor. Grounded in the experiential avoidance theory, this study investigates the mediating roles of cognitive fusion and negative emotions in the relationship between CV and NSSI, providing new insights into these key variables. Methods: A convenience sample of 457 undergraduate students (29% male; mean age 18.36±0.66 years) from two universities in Fujian Province participated in this study. Data were collected using the Cyberbullying Victimization Scale, Cognitive Fusion Questionnaire, Positive and Negative Affect Schedule, and Non-Suicidal Self-Injury Scale. Descriptive statistics and Pearson correlation analysis were conducted using SPSS 25.0, while the mediating effects were analyzed using Process 3.5. Results: (1) Significant positive correlations were found among CV, cognitive fusion, negative emotions, and NSSI (p < 0.01). (2) CV was directly associated with NSSI (ß = 0.22, p < 0.001) and positively predicted both cognitive fusion (ß = 0.17, p < 0.001) and negative emotions (ß = 0.15, p < 0.01). Additionally, cognitive fusion (ß = 0.16, p < 0.01) and negative emotions (ß = 0.11, p < 0.05) significantly predicted NSSI. (3) Mediation analyses revealed that cognitive fusion and negative emotions mediated the CV-NSSI relationship through three pathways: CV→cognitive fusion→NSSI (mediation effect = 0.026), CV→negative emotions→NSSI (mediation effect = 0.02), and CV→cognitive fusion→negative emotions→NSSI (mediation effect = 0.01). Conclusion: The study confirms that CV influences NSSI indirectly through cognitive fusion and negative emotions, supporting the experiential avoidance model. These findings underscore the importance of addressing cognitive and emotional processes in interventions aimed at reducing NSSI among college students.

Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects.

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

Elevated protein carbonylation and oxidative stress do not affect protein structure and function in the long-living naked-mole rat: a proteomic approach.

The 'oxidative stress theory of aging' predicts that aging is primarily regulated by progressive accumulation of oxidized macromolecules that cause deleterious effects to cellular homeostasis and induces a decline in physiological function. However, our reports on the detection of higher level of oxidized protein carbonyls in the soluble cellular fractions of long-living rodent naked-mole rats (NMRs, lifespan ~30yrs) compared to short-lived mice (lifespan ~3.5yrs) apparently contradicts a key tenet of the oxidative theory. As oxidation often inactivates enzyme function and induces higher-order soluble oligomers, we performed a comprehensive study to measure global protein carbonyl level in different tissues of age-matched NMRs and mice to determine if the traditional concept of oxidation mediated impairment of function and induction of higher-order structures of proteins are upheld in the NMRs. We made three intriguing observations with NMRs proteins: (1) protein carbonyl is significantly elevated across different tissues despite of its exceptional longevity, (2) enzyme function is restored despite of experiencing higher level of protein carbonylation, and (3) enzymes show lesser sensitivity to form higher-order non-reducible oligomers compared to short-living mouse proteins in response to oxidative stress. These observations were made based on the global analysis of protein carbonyl and identification of two heavily carbonylated proteins in the kidney, triosephosphate isomerase (TPI) and cytosolic peroxiredoxin (Prdx1). These un-expected intriguing observations thus strongly suggest that oxidative modification may not be the only criteria for impairment of protein and enzyme function; cellular environment is likely be the critical determining factor in this process and may be the underlying mechanism for exceptional longevity of NMR.

Heterologous Production in the Synechocystis Chassis Suggests the Biosynthetic Pathway of Astaxanthin in Cyanobacteria.

Astaxanthin is a carotenoid species with the highest antioxidant capability. Its natural resource is very rare. The biosynthesis of astaxanthin from ß-carotene includes a hydroxylation step and a ketolation step, for which the corresponding enzymes have been characterized in a few species. However, the sequence of these two reactions is unclear, and may vary with different organisms. In this study, we aimed to elucidate this sequence in Synechocystis, which is an ideal cyanobacterial synthetic biology chassis. We first silenced the endogenous carotene oxygenase gene SyneCrtO to avoid its possible interference in the carotenoid metabolic network. We then introduced the ß-carotene ketolase gene from Haematococcus pluvialis (HpBKT) and the CrtZ-type carotene ß-hydroxylase gene from Pantoea agglomerans (PaCrtZ) to this δCrtO strain. Our pigment analysis demonstrated that both the endogenous CrtR-type carotene hydroxylase SyneCrtR and HpBKT have the preference to use ß-carotene as their substrate for hydroxylation and ketolation reactions to produce zeaxanthin and canthaxanthin, respectively. However, the endogenous SyneCrtR is not able to further catalyze the 3,3'-hydroxylation of canthaxanthin to generate astaxanthin. From our results, a higher accumulation of canthaxanthin and a much lower level of astaxanthin, as confirmed using liquid chromatography-tandem mass spectrometry analysis, were detected in our transgenic BKT+/CrtZ+/δCrtO cells. Therefore, we proposed that the bottleneck for the heterologous production of astaxanthin in Synechocystis might exist at the hydroxylation step, which requires a comprehensive screening or genetic engineering for the corresponding carotene hydroxylase to enable the industrial production of astaxanthin.

Why is Smartphone Addiction More Common in Adolescents with Harsh Parenting? Depression and Experiential Avoidance's Multiple Mediating Roles.

Purpose: Harsh parenting is positively correlated with adolescents' smartphone addiction, according to a growing corpus of studies. The various mediating processes that could underlie this link, however, are not well understood. Based upon the experiential avoidance model, the current research aimed to identify the relation between harsh parenting and adolescents' smartphone addiction and the mediating roles of adolescents' depression and experiential avoidance. Methods: We recruited 456 adolescents (female = 52.6%; Mage = 13.19 years, SD = 0.85) at a public junior high school in China to complete the harsh discipline scale, 90-item Hopkins symptom checklist, acceptance and action questionnaire version II, and smartphone addiction scale short version. SPSS24.0 was used to conduct independent samples t-test, descriptive statistics, Pearson correlation analysis and common method bias test, PROCESS were used to conduct a significance test of the chain mediation effect on the data. Age, gender, and grade were used as con-founders that were controlled in order to make cautious predictions. Results: The results showed that (1) harsh parenting was positively correlated with adolescents' depression, experiential avoidance, and smartphone addiction; (2) both depression and experiential avoidance fully mediated the link between harsh parenting and smartphone addiction; and (3) depression and experiential avoidance also sequentially mediated the link between harsh parenting and smartphone addiction. These findings have significant implications for the prevention and intervention of adolescents' smartphone addiction. Conclusion: These findings suggested that harsh parenting may have an indirect impact on smartphone addiction in both a simple way (parallel mediation) and a complicated way (serial mediation). In addition, these studies shed light on smartphone addiction prevention and intervention.

Relationships Among Normative Beliefs About Aggression, Moral Disengagement, Self-Control and Bullying in Adolescents: A Moderated Mediation Model.

PURPOSE: Adolescent bullying has varying degrees of negative impact on both bullies and victims. Bullying in adolescents is complex, and the influence of individual factors and social factors should not be underestimated. Normative beliefs about aggression play an important role in adolescents' bullying. However, the mediating and moderating mechanisms underlying this association remain largely unknown. The current study investigated the mediating role of moral disengagement between normative beliefs about aggression and bullying, as well as the moderating role of self-control in this relationship from the perspective of individual cognition. METHODS: A sample of 491 Chinese adolescents (female = 38.9%; mean age = 13.05 years) were study participants. They completed questionnaires about normative beliefs about aggression, bullying, moral disengagement and self-control. SPSS21.0 statistical software was used to collate the obtained data, analyze descriptive statistics, and carry out reliability analysis and correlation analysis. RESULTS: Moral disengagement mediated the relationship between normative beliefs about aggression and bullying (ab=0.13, 95% CI=[0.07, 0.21]). The association between normative beliefs about aggression and moral disengagement was moderated by self-control (ß=-0.08, t=-2.25, p<0.05). The association between moral disengagement and bullying was moderated by self-control (ß=-0.09, t=-2.42, p<0.05). CONCLUSION: Results revealed that moral disengagement mediates the link between normative beliefs about aggression and bullying. Self-control moderated the relationship between normative beliefs about aggression and moral disengagement, and between moral disengagement and bullying.

How Does Parent-Adolescent Conflict and Deviant Peer Affiliation Affect Cyberbullying: Examining the Roles of Moral Disengagement and Gender.

Purpose: With the widespread use of the Internet and mobile phone, cyberbullying has become a new type of bullying among adolescents. It is of great practical significance to explore the relevant factors affecting cyberbullying for prevention and intervention of adolescents' cyberbullying. However, few studies have considered the effect of both the family and social factors on cyberbullying. Therefore, the current study examines whether the parent-adolescent conflict as a family factor and deviant peer affiliation as a social factor have an effect on adolescents' cyberbullying, as well as the role of moral disengagement and gender. Methods: A total of 777 middle school students (females = 336; mean age = 13.57; SD = 0.98) were surveyed by using the Parent-child Relationship Questionnaire, Deviant Peer Affiliation Questionnaire, Moral Disengagement Questionnaire and Cyber Bullying Behavior Questionnaire. SPSS21.0 was used to conduct descriptive statistics, Pearson correlation analysis and T-test, PROCESS were used to conduct significance test of moderated mediation effect on the data. Results: Parent-adolescent conflict does not directly predict cyberbullying. Moral disengagement played a complete mediating role between parent-adolescent conflict and cyberbullying, and gender played a moderating role between moral disengagement and cyberbullying. Deviant peer affiliation directly predict cyberbullying. Moral disengagement played a partially mediating role between parent-adolescent conflict and cyberbullying, and gender played a moderating role between moral disengagement and cyberbullying. Conclusion: Attention should be paid to the effect of moral disengagement on cyberbullying in family and social factors, as well as the role of gender.

Effect of acute TLR4 inhibition on insulin resistance in humans.

BackgroundStudies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.MethodsIn protocol I, 10 lean, healthy individuals received the following 72-hour i.v. infusions in a randomized crossover design: saline (30 mL/h) plus vehicle; Intralipid (30 mL/h) plus vehicle; or Intralipid (30 mL/h) plus eritoran (12 mg i.v. every 12 hours). In protocol II, also a randomized crossover design, 9 nondiabetic individuals with obesity received eritoran or vehicle for 72 hours. The effect of eritoran was assessed with euglycemic hyperinsulinemic clamps.ResultsIn protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG) concentrations, fasting plasma insulin (FPI) concentrations, and the homeostatic model assessment of insulin resistance (HOMA-IR) index by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations of these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in individuals with obesity and insulin resistance (protocol II).ConclusionsAcute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 in metabolic dysfunction in humans.Trial registrationClinicalTrials.gov NCT02321111 and NCT02267317.FundingNIH grants R01DK080157, P30AG044271, P30AG013319, and UL1TR002645.

One-Step In Situ Self-Assembly of Biodegradable Films for Long-Term Intravesical Bladder Cancer Therapy.

Intravesical instillation therapy is increasingly recognized as one of the most common clinical treatment strategies for bladder cancer. However, the antitumor efficacy of chemotherapy drugs is still limited due to their rapid clearance by periodic urination. To circumvent this issue, a drug-loaded thin film comprising the self-assembly of tannic acid (TA) and ferric ions (Fe3+) was in situ fabricated on the bladder wall in vivo. As expected, the TA@Fe film with adjustable thickness could effectively prolong the residence time of anticancer drugs in the bladder and realize sustained release of anticancer drugs. Together with the antibacterial properties, the TA@Fe film enabled improved chemotherapeutic efficacy. Moreover, the TA@Fe film caused no adverse effects on bladder function, demonstrating the in vivo biocompatibility. In addition, the T2 contrast effect of Fe3+ was employed to real-time monitor the disassembly of the TA@Fe film and the ensuing drug release process by magnetic resonance imaging. We believe that the TA@Fe-based drug delivery platform with enhanced retention in the bladder would be of great potential for treating various bladder diseases.

Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration.

Oxidative stress has been implicated in the etiology of age-related muscle loss (sarcopenia). However, the underlying mechanisms by which oxidative stress contributes to sarcopenia have not been thoroughly investigated. To directly examine the role of chronic oxidative stress in vivo, we used a mouse model that lacks the antioxidant enzyme CuZnSOD (Sod1). Sod1(-/-) mice are characterized by high levels of oxidative damage and an acceleration of sarcopenia. In the present study, we demonstrate that muscle atrophy in Sod1(-/-) mice is accompanied by a progressive decline in mitochondrial bioenergetic function and an elevation of mitochondrial generation of reactive oxygen species. In addition, Sod1(-/-) muscle exhibits a more rapid induction of mitochondrial-mediated apoptosis and loss of myonuclei. Furthermore, aged Sod1(-/-) mice show a striking increase in muscle mitochondrial content near the neuromuscular junctions (NMJs). Despite the increase in content, the function of mitochondria is significantly impaired, with increased denervated NMJs and fragmentation of acetylcholine receptors. As a consequence, contractile force in aged Sod1(-/-) muscles is greatly diminished. Collectively, we show that Sod1(-/-) mice display characteristics of normal aging muscle in an accelerated manner and propose that the superoxide-induced NMJ degeneration and mitochondrial dysfunction are potential mechanisms of sarcopenia.