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Measurements of the specific hear and the static dielectric permittivity of heptyloxycyanobiphenyl(7OCB) confined to the cylindrical pores of Anpore membranes in the isotropic phase are presented. Static dielectric measurements in bulk and submicrometer confinement on 7OCB are presented.

Carboxylesterase (CES) 2, an important metabolic enzyme, plays a critical role in drug biotransformation and lipid metabolism. Although CES2 is very important, few animal models have been generated to study its properties and functions. Rat Ces2 is similar to human CES2A - CES3A - CES4A gene cluster, with highly similar gene structure, function, and substrate. In this report, CRISPR-associated protein-9 (CRISPR/Cas9) technology was first used to knock out rat Ces2a , which is a main subtype of Ces2 mostly distributed in the liver and intestine. This model showed the absence of CES2A protein expression in the liver. Further pharmacokinetic studies of diltiazem, a typical substrate of CES2A, confirmed the loss of function of CES2A both in vivo and in vitro. At the same time, the expression of CES2C and CES2J protein in the liver decreased significantly. The body and liver weight of Ces2a knockout rats also increased, but the food intake did not change. Moreover, the deficiency of Ces2a led to obesity, insulin resistance, and liver fat accumulation, which are consistent with the symptoms of nonalcoholic fatty liver disease (NAFLD). Therefore, this rat model is not only a powerful tool to study drug metabolism mediated by CES2 but also a good disease model to study NAFLD. SIGNIFICANCE STATEMENT: Human carboxylesterase (CES) 2 plays a key role in the first-pass hydrolysis metabolism of most oral prodrugs as well as lipid metabolism. In this study, CRISPR/Cas9 technology was used to knock out Ces2a gene in rats for the first time. This model can be used not only in the study of drug metabolism and pharmacokinetics but also as a disease model of nonalcoholic fatty liver disease (NAFLD) and other metabolic disorders., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Colorectal cancer (CRC) is known to be the third most common cancer disease and the fourth-leading cause of cancer-related deaths worldwide. Bile acid, especially deoxycholic acid and lithocholic acid, were revealed to play an important role during carcinogenesis of CRC. In this study, we found organic solute transporter β (OST β ), an important subunit of a bile acid export transporter OST α -OST β , was noticeably downregulated in CRC. The decline of OST β expression in CRC was determined by Western blot and real-time polymerase chain reaction (RT-PCR), whereas chromatin immunoprecipitation (ChIP) was used to evaluate the histone acetylation state at the OST β promoter region in vivo and in vitro. CRC cell lines HT29 and HCT15 were treated with trichostation A (TSA) for the subsequent determination, including RT-PCR, small interfering RNA (siRNA) knockdown, ChIP, and dual-luciferase reporter gene assay, to find out which histone acetyltransferases and deacetylases exactly participated in regulation. We demonstrated that after TSA treatment, OST β expression increased noticeably because of upregulated H3K27Ac state at OSTβ promoter region. We found that stimulating the expression of p300 with CTB (Cholera Toxin B subunit, an activator of p300) and inhibiting p300 expression with C646 (an inhibitor of p300) or siRNA designed for p300 could control OST β expression through modulating H3K27Ac state at OSTβ promoter region. Therefore, downregulated expression of p300 in CRC may cause low expression of OST β in CRC via epigenetic regulation. Generally, we revealed a novel epigenetic mechanism underlying OST β repression in CRC, hoping this mechanism would help us to understand and inhibit carcinogenesis of CRC. SIGNIFICANCE STATEMENT: Organic solute transporter β ( OSTβ ) expression is lower in colon cancer tissues compared with adjacent normal tissues. We revealed the epigenetic mechanisms of it and proved that p300 controls OST β expression through modulating H3K27Ac state at OSTβ promoter region and hence causes low expression of OST β in colorectal cancer., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Mobile health interventions may support risk factor management and are readily scalable in healthcare systems. We aim to evaluate the efficacy of a text messaging-based intervention to improve glycemic control in patients with coronary heart disease and diabetes mellitus in China., Methods and Results: The CHAT-DM study (Cardiovascular Health and Texting-Diabetes Mellitus) was a parallel-group, single-blind, randomized clinical trial that included 502 patients with both coronary heart disease and diabetes mellitus from 34 hospitals in China. The intervention group (n=251) received 6 text messages per week for 6 months in addition to usual care. Messages were theory driven and culturally tailored to provide educational and motivational information on glucose monitoring, blood pressure control, medication adherence, physical activity, and lifestyle. The control group (n=251) received usual care and 2 thank you messages per month. The primary outcome was change in glycated hemoglobin (HbA 1C [hemoglobin A 1C ]) from baseline to 6 months. Secondary outcomes were change in proportion of patients achieving HbA 1C <7%, fasting blood glucose, systolic blood pressure, LDL (low-density lipoprotein) cholesterol, body mass index, and physical activity from baseline to 6 months. The end points were assessed using analyses of covariance. The follow-up rate was 99%. When compared with control group at 6 months, the intervention group had a greater reduction in HbA 1C (-0.2% versus 0.1%; P=0.003) and a greater proportion of participants who achieved HbA 1C <7% (69.3% versus 52.6%; P=0.004). Change in fasting blood glucose was larger in the intervention group (between-group difference: -0.6 mmol/L; 95% CI, -1.1 to -0.2; P=0.011), but no other outcome differences were observed. Nearly all participants reported that messages were easy to understand (97.1%) and useful (94.1%)., Conclusions: A text message intervention resulted in better glycemic control in patients with diabetes mellitus and coronary heart disease. While the mechanism of this benefit remains to be determined, the results suggest that a simple, culturally sensitive mobile text messaging program may provide an effective and feasible way to improve disease self-management., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02883842.

Potent and selective antagonists of the voltage-gated sodium channel Na V 1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human Na V 1.7 channels with an IC 50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC 50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other Na V family members, including Na V 1.4 expressed in muscle and Na V 1.5 expressed in the heart, as well as TTX-resistant Na V channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple Na V 1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective Na V 1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

CD4 + T helper cells, especially T helper 17 (T H 17) cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on proinflammatory cytokine interleukin 17 (IL-17) and interferon- γ (IFN- γ ) production. In this study, we screened BA derivatives and found a BA derivative, SH479, that had a greater inhibitory effect on T H 17 differentiation. Our further analysis showed that SH479 had a greater inhibitory effect on T H 17 and T H 1, and a more stimulatory effect on regulatory T (Treg) cells. To evaluate the effects of SH479 on autoimmune diseases in vivo, we employed the extensively used MS mouse model experimental autoimmune encephalomyelitis (EAE). Our results showed that SH479 ameliorated clinical and histologic signs of EAE in both prevention and therapeutic protocols by regulating the T H 17/Treg balance. SH479 dose-dependently reduced splenic lymphocyte proinflammatory factors and increased anti-inflammatory factors. Moreover, SH479 specifically inhibited splenic lymphocyte viability from EAE mice but not normal splenic lymphocyte viability. At the molecular level, SH479 inhibited T H 17 differentiation by regulating signal transducer and activator of transcription-3 (STAT3) phosphorylation, DNA binding activity, and recruitment to the Il-17a promoter in CD4 + T cells. Furthermore, SH479 promoted the STAT5 signaling pathway and inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B) signaling pathway. Together, our data demonstrated that SH479 ameliorated EAE by regulating the T H 17/Treg balance through inhibiting the STAT3 and NF- κ B pathways while activating the STAT5 pathway, suggesting that SH479 is a potential novel drug candidate for autoimmune diseases including MS., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

The prevalence of obesity has markedly increased worldwide. Obese patients pose significant challenges to anesthesiologists with regard to accurate dosing of anesthetics due to potentially altered pharmacokinetics (PK). Here we determined the PK and pharmacodynamics (PD) of propofol for anesthesia induction in morbidly obese (MO) subjects (body mass index >35 kg/m(2)) at two dosing regimens: dosing based on total body weight and lean body weight (LBW), respectively. The propofol pharmacokinetic profile was well fitted with a two-compartment model. Both elimination clearance (223%-243% of controls, who had a body mass index <25 kg/m(2); P < 0.01) and peripheral compartment volume (156%-180% of controls; P < 0.01) were significantly increased in MO subjects, resulting in an equal or decreased propofol level in plasma (total body weight-based dosing). Furthermore, propofol PD (measured by the bispectral index) was adequately described by a PK/PD model that linked an effect compartment to the two-compartment PK model through a sigmoidal Emax model. All PD parameters except EC50 values (the half maximal effect concentration) were similar (P > 0.05) between MO subjects and controls. Morbid obesity led to a significant decrease (37.9%-38.6%; P < 0.01) in EC50 values, which suggests increased brain sensitivity to propofol in the MO population. Moreover, dose reduction (i.e., dosing based on LBW) generated identical anesthetic effects in MO subjects compared with controls. In conclusion, morbid obesity significantly altered both PK and PD of propofol. LBW was a better weight-based dosing scalar for anesthesia induction with propofol in MO subjects., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders., (Copyright © 2016 by The Author(s).)

The ability to rapidly switch the intracellular energy storage form from starch to lipids is an advantageous trait for microalgae feedstock. To probe this mechanism, we sequenced the 56.8-Mbp genome of Chlorella pyrenoidosa FACHB-9, an industrial production strain for protein, starch, and lipids. The genome exhibits positive selection and gene family expansion in lipid and carbohydrate metabolism and genes related to cell cycle and stress response. Moreover, 10 lipid metabolism genes might be originated from bacteria via horizontal gene transfer. Transcriptomic dynamics tracked via messenger RNA sequencing over six time points during metabolic switch from starch-rich heterotrophy to lipid-rich photoautotrophy revealed that under heterotrophy, genes most strongly expressed were from the tricarboxylic acid cycle, respiratory chain, oxidative phosphorylation, gluconeogenesis, glyoxylate cycle, and amino acid metabolisms, whereas those most down-regulated were from fatty acid and oxidative pentose phosphate metabolism. The shift from heterotrophy into photoautotrophy highlights up-regulation of genes from carbon fixation, photosynthesis, fatty acid biosynthesis, the oxidative pentose phosphate pathway, and starch catabolism, which resulted in a marked redirection of metabolism, where the primary carbon source of glycine is no longer supplied to cell building blocks by the tricarboxylic acid cycle and gluconeogenesis, whereas carbon skeletons from photosynthesis and starch degradation may be directly channeled into fatty acid and protein biosynthesis. By establishing the first genetic transformation in industrial oleaginous C. pyrenoidosa, we further showed that overexpression of an NAD(H) kinase from Arabidopsis (Arabidopsis thaliana) increased cellular lipid content by 110.4%, yet without reducing growth rate. These findings provide a foundation for exploiting the metabolic switch in microalgae for improved photosynthetic production of food and fuels., (© 2015 American Society of Plant Biologists. All Rights Reserved.)

Rationale: Impaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system, but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases, thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor cullin-RING ligases is known to regulate the degradation of cytosolic misfolded proteins., Objective: We sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy., Methods and Results: Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8(hypo)) mice were used. Myocardial neddylated forms of cullins were markedly increased, and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8 hypomorphism. When introduced into proteinopathic mice in which a bona fide misfolded protein R120G missense mutation of αβ-crystallin (CryAB(R120G)) is overexpressed in the heart, CSN8 hypomorphism aggravated CryAB(R120G)-induced restrictive cardiomyopathy and shortened the lifespan of CryAB(R120G) mice, which was associated with augmented accumulation of protein aggregates, increased neddylated proteins, and reduced levels of total ubiquitinated proteins and LC3-II in the heart. In cultured cardiomyocytes, both CSN8 knockdown and cullin-RING ligase inactivation suppressed the ubiquitination and degradation of CryAB(R120G) but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryAB(R120G) cytotoxicity., Conclusions: (1) CSN8/CSN promotes the ubiquitination and degradation of misfolded proteins and protects against cardiac proteotoxicity, and (2) cullin-RING ligases participate in degradation of cytosolic misfolded proteins., (© 2015 American Heart Association, Inc.)

Context: Associations between sleep, daytime nap duration, and osteoporosis remain uncertain, and far less is even known about the influence of sex, menopause, and sleep quality on them., Objective: The objective of the study was to test the associations between sleep, daytime nap duration, and osteoporosis and whether they vary by sex, menopause, and sleep quality., Design, Setting, and Patients: This cross-sectional study was based on two communities in China. A total of 8688 participants (3950 males and 4738 females) aged 40 years or older were enrolled in the study., Main Outcomes Measures: Self-reported sleep duration, daytime nap duration, sleep quality, and calcaneus bone mineral density were recorded., Results: Sleep duration of 8-9 h/d and nap duration of 0 min/d were regarded as reference values. In postmenopausal women, risks (odds ratio and 95% confidence interval) of osteoporosis for sleep durations of 7-8 h/d, 9-10 h/d, and 10 h/d or longer were 1.531 (1.106, 2.121), 1.360 (1.035, 1.787), and 1.569 (1.146, 2.149), respectively (P < .05), and risks of osteoporosis for daytime nap durations of 30-60 min/d and longer than 60 min/d were 1.553 (1.212-1.989) and 1.645 (1.250-2.165), respectively (P < .05). However, a significant difference was not consistently observed in men or premenopausal women, regardless of sleep or daytime nap duration. As for sleep quality, positive results were seen most remarkably in postmenopausal females with good sleep., Conclusions: Sleep durations of 7-8 h/d, 9-10 h/d, and 10 h/d or longer, as well as longer daytime napping times, tend to present higher risks of having osteoporosis, and this tendency is most obvious in postmenopausal women reporting good-quality sleep.