Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet.

BACKGROUND: Hepatocyte nuclear factor 4α (HNF4α) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study aimed to elucidate the role of down-regulation of HNF4α and GR in fatty liver and hyperlipidemia. METHODS: Adult mice with liver-specific heterozygote (HET) and knockout (KO) of HNF4α or GR were fed a high-fat-high-sugar diet (HFHS) for 15 days. Alterations in hepatic and circulating lipids were determined with analytical kits, and changes in hepatic mRNA and protein expression in these mice were quantified by real-time PCR and Western blotting. Serum and hepatic levels of bile acids were quantified by LC-MS/MS. The roles of HNF4α and GR in regulating hepatic gene expression were determined using luciferase reporter assays. RESULTS: Compared to HFHS-fed wildtype mice, HNF4α HET mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4α KO mice had fatty liver but mild hypolipidemia, down-regulation of lipid-efflux genes, and induction of genes for uptake, synthesis, and storage of lipids. Serum levels of chenodeoxycholic acid and deoxycholic acid tended to be decreased in the HNF4α HET mice but dramatically increased in the HNF4α KO mice, which was associated with marked down-regulation of cytochrome P450 7a1, the rate-limiting enzyme for bile acid synthesis. Hepatic mRNA and protein expression of sterol-regulatory-element-binding protein-1 (SREBP-1), a master lipogenic regulator, was induced in HFHS-fed HNF4α HET mice. In reporter assays, HNF4α cooperated with the corepressor small heterodimer partner to potently inhibit the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Hepatic nuclear GR proteins tended to be decreased in the HNF4α KO mice. HFHS-fed mice with liver-specific KO of GR had increased hepatic lipids and induction of SREBP-1C and PPARγ, which was associated with a marked decrease in hepatic levels of HNF4α proteins in these mice. In reporter assays, GR and HNF4α synergistically/additively induced lipid catabolic genes. CONCLUSIONS: induction of lipid catabolic genes and suppression of lipogenic genes by HNF4α and GR may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.

Urinary BA Indices as Prognostic Biomarkers for Complications Associated with Liver Diseases.

Hepatobiliary diseases and their complications cause the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues, which may exacerbate the underlying condition and lead to unfavorable prognosis. To develop and validate prognostic biomarkers for the prediction of complications of cholestatic liver disease based on urinary BA indices, liquid chromatography-tandem mass spectrometry was used to analyze urine samples from 257 patients with cholestatic liver diseases during a 7-year follow-up period. The urinary BA profile and non-BA parameters were monitored, and logistic regression models were used to predict the prognosis of hepatobiliary disease-related complications. Urinary BA indices were applied to quantify the composition, metabolism, hydrophilicity, and toxicity of the BA profile. We have developed and validated the bile-acid liver disease complication (BALDC) model based on BA indices using logistic regression model, to predict the prognosis of cholestatic liver disease complications including ascites. The mixed BA and non-BA model was the most accurate and provided higher area under the receiver operating characteristic (ROC) and smaller akaike information criterion (AIC) values compared to both non-BA and MELD (models for end stage liver disease) models. Therefore, the mixed BA and non-BA model could be used to predict the development of ascites in patients diagnosed with liver disease at early stages of intervention. This will help physicians to make a better decision when treating hepatobiliary disease-related ascites.

Hand Gesture Recognition on a Resource-Limited Interactive Wristband.

Most of the reported hand gesture recognition algorithms require high computational resources, i.e., fast MCU frequency and significant memory, which are highly inapplicable to the cost-effectiveness of consumer electronics products. This paper proposes a hand gesture recognition algorithm running on an interactive wristband, with computational resource requirements as low as Flash < 5 KB, RAM < 1 KB. Firstly, we calculated the three-axis linear acceleration by fusing accelerometer and gyroscope data with a complementary filter. Then, by recording the order of acceleration vectors crossing axes in the world coordinate frame, we defined a new feature code named axis-crossing code. Finally, we set templates for eight hand gestures to recognize new samples. We compared this algorithm's performance with the widely used dynamic time warping (DTW) algorithm and recurrent neural network (BiLSTM and GRU). The results show that the accuracies of the proposed algorithm and RNNs are higher than DTW and that the time cost of the proposed algorithm is much less than those of DTW and RNNs. The average recognition accuracy is 99.8% on the collected dataset and 97.1% in the actual user-independent case. In general, the proposed algorithm is suitable and competitive in consumer electronics. This work has been volume-produced and patent-granted.

Chiral Indolizidine Synthesis through the Ir-Catalyzed Asymmetric Hydrogenation of Cyclic Pyridinium Salts.

The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)pyridines proceeded smoothly in the presence of [Ir(cod)Cl]2 and (R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines 6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The enantiomeric purity of 6j was increased to 92:8 through recrystallization.

Lipophilic nanocrystal prodrug-release defines the extended pharmacokinetic profiles of a year-long cabotegravir.

A once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.

Bile acid indices as biomarkers for liver diseases II: The bile acid score survival prognostic model.

BACKGROUND: Cholestatic liver diseases are characterized by an accumulation of toxic bile acids (BA) in the liver, blood and other tissues which lead to progressive liver injury and poor prognosis in patients. AIM: To discover and validate prognostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS: We analyzed urine samples by liquid chromatography-tandem mass spectrometry and investigated the use of the urinary BA profile to develop survival models that can predict the prognosis of hepatobiliary diseases. The urinary BA profile, a set of non-BA parameters, and the adverse events of liver transplant and/or death were monitored in 257 patients with cholestatic liver diseases for up to 7 years. The BA profile was characterized by calculating BA indices, which quantify the composition, metabolism, hydrophilicity, formation of secondary BA, and toxicity of the BA profile. We have developed and validated the bile-acid score (BAS) model (a survival model based on BA indices) to predict the prognosis of cholestatic liver diseases. RESULTS: We have developed and validated a survival model based on BA (the BAS model) indices to predict the prognosis of cholestatic liver diseases. Our results demonstrate that the BAS model is more accurate and results in higher true-positive and true-negative prediction of death compared to both non-BAS and model for end-stage liver disease (MELD) models. Both 5- and 3-year survival probabilities markedly decreased as a function of BAS. Moreover, patients with high BAS had a 4-fold higher rate of death and lived for an average of 11 mo shorter than subjects with low BAS. The increased risk of death with high vs low BAS was also 2-4-fold higher and the shortening of lifespan was 6-7-mo lower compared to MELD or non-BAS. Similarly, we have shown the use of BAS to predict the survival of patients with and without liver transplant (LT). Therefore, BAS could be used to define the most seriously ill patients, who need earlier intervention such as LT. This will help provide guidance for timely care for liver patients. CONCLUSION: The BAS model is more accurate than MELD and non-BAS models in predicting the prognosis of cholestatic liver diseases.

Bile acid indices as biomarkers for liver diseases I: Diagnostic markers.

BACKGROUND: Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. AIM: To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS: We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases. RESULTS: Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. CONCLUSION: BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.

A Strategy for Amide C-N Bond Activation with Ruthenium Catalyst: Selective Aromatic Acylation.

A strategy for amide C-N bond activation with ruthenium catalyst is described for the first time. The in situ formed bis-cycloruthenated complexes were demonstrated to be the key active species with superior oxidative addition ability to an inert amide C-N bond. The direct C-H bond activation of 2-arylpyridines followed by the amide C-N bond activation took place in the presence of a ruthenium precatalyst to produce monoacylation products in moderate to good yields. Synthetically useful functional groups, such as halogen atoms (F and Cl), ester, acetyl, and vinyl, remained intact during tandem C-H/C-N bond activation reactions.

catena-Poly[[trimethyl-tin(IV)]-µ-2-(2-chloro-phenyl)-acetato].

In the title polymeric coordination compound, [Sn(CH(3))(3)(C(8)H(6)ClO(2))](n), the Sn atoms exhibit a distorted trigonal-bipyramidal geometry with the carboxyl-ate O atoms of the 2-chloro-phenyl-acetato ligands in axial positions and with the equatorial sites occupied by the three methyl groups. Adjacent Sn atoms are bridged by coordination to the two O atoms of each 2-chloro-phenyl-acetato ligand, forming a chain structure.

3,3'-Oxybi[isobenzofuran-1(3H)-one].

The title compound, C(16)H(10)O(5), consists of two isobenzofuran-1(3H)-one moieties which are linked by a bridging O atom. The two halves of the mol-ecule display approximate non-crystallographic mirror symmetry. The dihedral angle between the two isobenzofuran-1(3H)-one ring systems is 53.18 (6) Å. Two chiral carbon centres are observed in the compound, but their absolute configurations could not be determined. In the crystal structure, inter-molecular C-H⋯O hydrogen bonds link mol-ecules into zigzag chains along c. Additional C-H⋯O inter-actions connect adjacent chains.

(E)-2-(Isonicotinoylhydrazonometh-yl)benzoic acid methanol monosolvate.

The title compound, C(14)H(11)N(3)O(3)·CH(4)O, was synthesized by the condensation reaction of isonicotinohydrazide with an equimolar quantity of 2-formyl-benzoic acid in methanol. The hydrazone mol-ecule displays an E configuration about the C=N bond. The dihedral angel between the pyridine and the benzene rings is 12.04 (5)°. In the crystal structure, mol-ecules are linked by O-H⋯N, O-H⋯O and N-H⋯O hydrogen-bonding inter-actions.

3-[(3-Oxo-1,3-dihydro-isobenzofuran-1-yl)amino]benzoic acid.

In the title compound, C(15)H(11)NO(4), the dihedral angle formed by the benzene ring and isobenzofuran ring system is 67.82 (5) Å. The crystal structure is stabilized by inter-molecular O-H⋯O and N-H⋯O hydrogen-bonding inter-actions.

3-Eth-oxy-2-(1,3-thia-zol-2-yl)isoindolin-1-one.

In the title compound, C(13)H(12)N(2)O(2)S, the dihedral angles between the isoindolone ring system and the thia-zole ring and the eth-oxy group are 6.50 (11) and 89.0 (2)°, respectively.

Octa-butyl-bis{(E)-2-[4-(2-hydroxy-benzyl-ideneamino)phen-yl]acetato}di-µ(2)-methoxo-di-µ(3)-oxido-tetra-tin(IV).

The title compound, [Sn(4)(C(4)H(9))(8)(C(15)H(12)NO(3))(2)(CH(3)O)(2)O(2)], is a centrosymmetric dimer and displays a ladder type structural motif. There are four Sn(IV) centres which can be divided into two sorts, viz. two endocyclic and two exocyclic. The endo- and exocyclic Sn(IV) centres are linked by bidentate deprotonated methanol and µ(3)-O atoms. Each exocyclic Sn(IV) centre is also coordinated by a monodentate 2-[4-(2-hydroxy-benzyl-idene-amino)phen-yl]acetate ligand. Parts of the butyl groups were found to be disordered over two sets of sites.

µ-2-Amino-terephthalato-κO:O-bis-[triphenyl-tin(IV)].

The title compound, [Sn(2)(C(6)H(5))(6)(C(8)H(5)NO(4))], contains two triphenyl-tin groups bridged by a 2-amino-terephthalate ligand. The two Sn(IV) centers have similar distorted tetra-hedral coordination geometries. Each Sn(IV) atom is bonded to three phenyl C atoms and one O atom from a carboxyl-ate group. The other O atom of the carboxyl-ate group has a weak inter-action with the Sn atom. The amino group is disordered over two sites, with site-occupancy factors of 0.779 (11) and 0.221 (11). Intra-molecular N-H⋯O hydrogen bonds are observed.

N'-[(E)-3-Pyridylmethyl-idene]benzo-hydrazide.

The title compound, C(13)H(11)N(3)O, was prepared by the reaction of benzohydrazide and nicotinaldehyde. The dihedral angle between the planes of the two aromatic rings is 47.78 (9)°. The crystal structure is stabilized by inter-molecular N-H⋯N hydrogen-bonding inter-actions.

(E)-2-Meth-oxy-6-(thia-zol-2-ylimino-meth-yl)phenol.

The title compound, C(11)H(10)N(2)O(2)S, displays an E configuration about the C=N bond. The mean planes of the thia-zole and benzene rings make a dihedral angle of 9.32 (18)°. Intra-molecular O-H⋯N hydrogen bonds are found in the crystal structure.

catena-Poly[[trimethyl-tin(IV)]-µ-2,5-difluoro-benzoato-κO:O'].

In the title polymeric coordination compound, [Sn(CH(3))(3)(C(7)H(3)F(2)O(2))](n), the Sn atom exhibits a distorted trigonal-bipyramidal coordination geometry with the carboxyl-ate O atoms in the axial positions and the equatorial positions occupied by the methyl groups. The two Sn-O bond lengths are 2.225 (5) and 2.410 (6) Å.

catena-Poly[[trimethyl-tin(IV)]-µ-2,4,6-trichloro-benzoato].

In the title compound, [Sn(CH(3))(3)(C(7)H(2)Cl(3)O(2))](n), the tin(IV) atom exhibits a slightly distorted trigonal-bipyramidal geometry with two O atoms of symmetry-related carboxyl-ate groups in the axial positions and three methyl groups in the equatorial positions. In the crystal structure, the metal atoms are linked by carboxyl-ate bridges into polymeric chains extending along the b axis.

Tris(O-cyclo-hexyl dithio-carbonato-κS)anti-mony(III).

In the mol-ecule of the title compound, [Sb(C(7)H(11)OS(2))(3)], the anti-mony(III) is coordinated by the S atoms of three O-alkyl xanthate groups acting as monodentate ligands, forming a distorted trigonal-pyramidal coordination.