Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease.

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12µM for hMAO-A and 0.816µM for hMAO-B), moderate inhibition of Aß aggregation (75.1% at 20µM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.

Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer's disease.

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.

A Novel Score Based on Controlled Attenuation Parameter Accurately Predicts Hepatic Steatosis in Individuals With Metabolic Dysfunction Associated Steatotic Liver Disease: A Derivation and Independent Validation Study.

INTRODUCTION: In metabolic dysfunction-associated steatotic liver disease, the diagnostic efficacy of controlled attenuation parameter (CAP) was not very accurate in evaluating liver fat content. The aim of this study was to develop a score, based on CAP and conventional clinical parameters, to improve the diagnostic performance of CAP regarding liver fat content. METHODS: A total of 373 participants from 2 independent Chinese cohorts were included and divided into derivation (n = 191), internal validation (n = 75), and external validation (n = 107) cohorts. Based on the significant difference index between the 2 groups defined by the magnetic resonance imaging-proton density fat fraction (MRI-PDFF) in derivation cohort, the optimal model (CAP-BMI-AST score [CBST]) was screened by the number of parameters and the area under the receiver operating characteristic curve (AUROC). In the internal and external validation cohorts, the AUROC and corresponding 95% confidence intervals (CIs) were used to compare the diagnostic performance of CBST with that of CAP. RESULTS: We constructed the CBST = -14.27962 + 0.05431 × CAP - 0.14266 × body mass index + 0.01715 × aspartate aminotransferase. When MRI-PDFF was ≥20%, ≥10%, and ≥5%, the AUROC for CBST was 0.77 (95% CI 0.70-0.83), 0.89 (95% CI 0.83-0.94), and 0.93 (95% CI 0.88-0.98), which was higher than that for CAP respectively. In the internal validation cohort, the AUROC for CBST was 0.80 (95% CI 0.70-0.90), 0.95 (95% CI 0.91-1.00), and 0.98 (95% CI 0.94-1.00). The optimal thresholds of CBST were -0.5345, -1.7404, and -1.9959 for detecting MRI-PDFF ≥20%, ≥10%, and ≥5%, respectively. DISCUSSION: The CBST score can accurately evaluate liver steatosis and is superior to the CAP.

Rice protein exerts a hypocholesterolemic effect through regulating cholesterol metabolism-related gene expression and enzyme activity in adult rats fed a cholesterol-enriched diet.

The major aim of this study is to elucidate the hypocholesterolemic mechanism exerted by rice protein (RP) in adult rats under cholesterol-enriched dietary condition. Compared with casein, the cholesterol levels in plasma and the liver were significantly reduced by RP, accompanying significant inhibition of cholesterol absorption. RP increased the activity and mRNA level of cholesterol 7α-hydroxylase, whereas acyl-CoA:cholesterol acyltransferase activity and gene expression were significantly depressed with consumption of RP. Neither the activity nor gene expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase of RP differed from that of casein. The gene expression of the peroxisome proliferator-activated receptor α and liver X receptor α were significantly activated by consumption of RP. RP did not modify the mRNA level of sterol regulatory element-binding protein-2 with respect to casein. These results suggest RP can induce a cholesterol-lowering effect through modifying cholesterol metabolism-related gene expression and enzyme activity in adult rats.

Rice protein improves adiposity, body weight and reduces lipids level in rats through modification of triglyceride metabolism.

BACKGROUND: To elucidate whether rice protein can possess a vital function in improving lipids level and adiposity, the effects of rice proteins extracted by alkaline (RP-A) and α-amylase (RP-E) on triglyceride metabolism were investigated in 7-week-old male Wistar rats fed cholesterol-enriched diets for 2 weeks, as compared with casein (CAS). RESULTS: Compared with CAS, plasma concentrations of glucose and lipids were significantly reduced by RP-feeding (P < 0.05), as well as hepatic accumulation of lipids (P < 0.05). RP-A and RP-E significantly depressed the hepatic activities of fatty acid synthase (FAS), glucose 6-phosphate dehydrogenase (G6PD) and malate dehydrogenase (MDH) (P < 0.05), whereas the activities of lipoprotein lipase (PL) and hepatic lipase (HL) were significantly stimulated (P < 0.05), as compared to CAS. Neither lipids level nor activities of enzymes were different between RP-A and RP-E (P > 0.05). There was a significant positive correlation between protein digestibility and deposit fat (r = 0.8567, P < 0.05), as well as the plasma TG concentration (r = 0.8627, P < 0.05). CONCLUSIONS: The present study demonstrates that rice protein can modify triglyceride metabolism, leading to an improvement of body weight and adiposity. Results suggest that the triglyceride-lowering action as well as the potential of anti-adiposity induced by rice protein is attributed to upregulation of lipolysis and downregulation of lipogenesis, and the lower digestibility of rice protein may be the main modulator responsible for the lipid-lowering action.

Comparative Analysis of Clinical and Medication Information between Chronic Hepatitis B Patients with Damp Heat Syndrome and Spleen Deficiency Syndrome.

Traditional Chinese medicine (TCM) has a long history in the treatment of chronic hepatitis B (CHB) based on the syndrome identification. Previous studies reported CHB patients with damp-heat (DH) syndrome accompanied with a severe liver function damage, but lacked the medication analysis. In this study, we analyzed 999 CHB patients with unidentified individual-level data from database to explore clinical features of two common syndromes of CHB patients based on the real world. Compared with the spleen deficiency (SD) syndrome, the CHB patients with DH syndrome had a significantly higher level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.05) but took more immunomodulators and hepatoprotective drugs (P < 0.1). Similarly, in the follow-up of 207 patients after 3 months, the improvement trend of ALT and AST of patients with sustained SD syndrome was significantly better than those whose TCM syndrome changed from SD to DH (P < 0.05). The logistic model indicated DH syndrome was a significant negative factor for reducing ALT level in CHB patients (OR = 4.854, P=0.032). This study suggests that CHB patients with DH syndrome have potentially more serious and sustained liver damage than the SD syndrome, which provides a reference for the personalized management of CHB patients from the perspective of TCM syndromes.

Synthesis and evaluation of isoprenylation-resveratrol dimer derivatives against Alzheimer's disease.

A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. Biological analysis revealed that these derivatives had moderate inhibitory activity against human monoamine oxidase B (hMAO-B). In particular, 3 and 7 showed the better inhibitory activity for hMAO-B (IC50 = 3.91 ±â€¯0.23 µM, 0.90 ±â€¯0.01 µM) respectively. Compound 3 (IC50 = 46.95 ±â€¯0.21 µM for DPPH, 1.43 and 1.74 trolox equivalent by ABTS and FRAP method respectively), and 7 (IC50 = 35.33 ±â€¯0.15 µM for DPPH, 1.70 and 1.97 trolox equivalent by ABTS method and FRAP method respectively) have excellent antioxidant effects. Cellular assay shown that 3 and 7 had lower toxicity and were resistant to neurotoxicity induced by oxidative toxins (H2O2, rotenone and oligomycin-A). More importantly, the selected compounds have neuroprotective effects against ROS generation, H2O2-induced apoptosis and a significant in vitro anti-inflammatory activity. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that 3 and 7 would be predominant to cross the blood-brain barrier. In this study, mouse microglia BV2 cells were used to establish cell oxidative stress injury model with H2O2 and to explore the protective effect and mechanism of 3 and 7. In general, 3 and 7 can be considered candidates for potential treatment of AD.

Donepezil-butylated hydroxytoluene (BHT) hybrids as Anti-Alzheimer's disease agents with cholinergic, antioxidant, and neuroprotective properties.

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC50, 0.075 µM for eeAChE and 0.75 µM for hAChE) and Monoamine oxidase B (MAO-B) inhibition (IC50, 7.4 µM for hMAO-B), excellent antioxidant activity (71.7 µM of IC50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, hAChE-induced Aß aggregation. Moreover, 7d possessed neuroprotective potency against H2O2-induced oxidative damage on PC12 cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD.

Altered oral microbiota in chronic hepatitis B patients with different tongue coatings.

AIM: To elucidate tongue coating microbiota and metabolic differences in chronic hepatitis B (CHB) patients with yellow or white tongue coatings. METHODS: Tongue coating samples were collected from 53 CHB patients (28 CHB yellow tongue coating patients and 25 CHB white tongue coating patients) and 22 healthy controls. Microbial DNA was extracted from the tongue samples, and the bacterial 16S ribosomal RNA gene V3 region was amplified from all samples and sequenced with the Ion Torrent PGM™ sequencing platform according to the standard protocols. The metabolites in the tongue coatings were evaluated using a liquid chromatography-mass spectrometry (LC-MS) platform. Statistical analyses were then performed. RESULTS: The relative compositions of the tongue coating microbiotas and metabolites in the CHB patients were significantly different from those of the healthy controls, but the tongue coating microbiota abundances and diversity levels were not significantly different. Compared with the CHB white tongue coating patients, the CHB yellow tongue coating patients had higher hepatitis B viral DNA (HBV-DNA) titers (median 21210 vs 500, respectively, P = 0.03) and a significantly lower level of Bacteroidetes (20.14% vs 27.93%, respectively, P = 0.013) and higher level of Proteobacteria (25.99% vs 18.17%, respectively, P = 0.045) in the microbial compositions at the phylum level. The inferred metagenomic pathways enriched in the CHB yellow tongue coating patients were mainly those involved in amino acid metabolism, which was consistent with the metabolic disorder. The abundances of bacteria from Bacteroidales at the order level were higher in the CHB white tongue coating patients (19.2% vs 27.22%, respectively, P = 0.011), whereas Neisseriales were enriched in the yellow tongue coating patients (21.85% vs 13.83%, respectively, P = 0.029). At the family level, the abundance of Neisseriaceae in the yellow tongue patients was positively correlated with the HBV-DNA level but negatively correlated with the S-adenosyl-L-methionine level. CONCLUSION: This research illustrates specific clinical features and bacterial structures in CHB patients with different tongue coatings, which facilitates understanding of the traditional tongue diagnosis.

Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-ß aggregation for the treatment of Alzheimer's disease.

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-ß (Aß) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 µM for MAO-B; 3.275 ± 0.040 µM for MAO-A) and Aß1-42 aggregation (54.0 ± 1.1%, 25 µM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.

Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.

Synthesis and pharmacological evaluation of multi-functional homoisoflavonoid derivatives as potent inhibitors of monoamine oxidase B and cholinesterase for the treatment of Alzheimer's disease.

A series of homoisoflavonoid derivatives was designed, synthesized and evaluated as potential multi-functional anti-Alzheimer's agents for their inhibitory activity on cholinesterase and monoamine oxidase. Among them, compound 16 showed moderate acetylcholinesterase (AChE) inhibitory activity (eeAChE IC50 = 0.89 ± 0.02 µM; hAChE IC50 = 0.657 ± 0.002 µM) and significant monoamine oxidase B (MAO-B) inhibitory activity (hMAO-B IC50 = 0.0372 ± 0.0002 µM). Kinetic analysis of AChE, MAO-B inhibition and molecular modeling studies revealed that compound 16 is a dual binding site inhibitor of AChE and noncompetitive inhibitor of MAO-B. Furthermore, 16 could penetrate through the blood-brain barrier (BBB) in vitro. Most importantly, oral administration of 16 demonstrated no marked signs of acute toxicity and it could significantly reverse scopolamine-induced memory impairment in mice. These results suggested that compound 16 is a promising multifunctional drug candidate with potential effect for the treatment of Alzheimer's disease.

Complete mitochondrial genome of blackedge greeneye Chlorophthalmus nigromarginatus (Aulopiformes, Chlorophthalmidae).

In this paper, the complete mitochondrial genome of Chlorophthalmus nigromarginatus has been determined. The mitochondrial genome (17,663 bp) had the canonical mitochondrial gene content and arrangement, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non-coding regions. The overall base composition of the heavy-strand is 25.66% A, 25.71% T, 17.82% G, and 30.81% C, with an AT content of 51.37%. It shared 86.6% identities with Chlorophthalmus agassizi. The phylogenetic analyses indicated the close relationship between the mitochondrial genome we presented and other species in order Aulopiformes.

Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aß interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aß1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 µM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aß1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

Antioxidant capacity responsible for a hypocholesterolemia is independent of dietary cholesterol in adult rats fed rice protein.

Dietary cholesterol and aging are major risk factors to accelerate oxidation process for developing hypercholesterolemia. The major aim of this study is to elucidate the effects of rice protein on cholesterol level and oxidative stress in adult rats fed with and without cholesterol. After 2 weeks of feeding, hepatic and plasma contents of cholesterol, reduced glutathione (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA) and protein carbonyl (PCO) were measured. In liver, total antioxidative capacity (T-AOC), activities of antioxidant enzymes (total superoxide dismutase, T-SOD; catalase, CAT), glutathione metabolizing enzyme activities and gene expression levels (γ-glutamylcysteine synthetase, γ-GCS; glutathione reductase, GR; glutathione peroxidase, GPx) were determined. Under cholesterol-free/enriched dietary condition, T-AOC, activities of T-SOD and CAT, glutathione metabolism related enzymes' activities and mRNA levels (γ-GCS, GR and GPx) were effectively stimulated by rice proteins as compared to caseins. Compared with caseins, rice proteins significantly increased hepatic and plasma GSH contents, whereas hepatic and plasma accumulations of MDA, PCO and GSSG were significantly reduced by rice protein-feedings. As a result, the marked reductions of cholesterol in the plasma and in the liver were observed in adult rats fed rice proteins with and without cholesterol. The present study demonstrates that the hypocholesterolemic effect of rice protein is attributable to inducing antioxidative response and depressing oxidative damage in adult rats fed cholesterol-free/enriched diets. Results suggest that the antioxidant capability involved in the hypocholesterolemic action exerted by rice protein is independent of dietary cholesterol during adult period.

Dietary freeze-dried black raspberry's effect on cellular antioxidant status during reflux-induced esophagitis in rats.

INTRODUCTION: Esophageal cancer consists of two distinct types, esophageal adenocarcinoma (EAC) and squamous cell carcinoma, both of which differ significantly in their etiology. Freeze-dried black raspberry (BRB) has been consistent in its ability to modulate the biomarkers and reduce the incidence of carcinogen-induced squamous cell carcinoma in rats. In our previous studies in the esophagoduodenal anastomosis (EDA) model, we have shown that the early modulation of manganese superoxide dismutase (MnSOD) significantly correlates with the development of reflux-induced EAC in rats. In this study we looked at the short-term effects of a BRB-supplemented diet on the modulation of antioxidant enzymes in reflux-induced esophagitis. METHODS: Male SD rats (8 wk old; n = 3-5) were randomized into three groups--sham-operated, fed control AIN-93M diet (SH-CD), EDA operated and fed either control diet (EDA-CD) or 2.5% (w/w) BRB diet (EDA-BRB). The effect of both reflux and dietary supplementation was analyzed 2 and 4 wk after EDA surgery. RESULTS: Animals in the EDA groups had significantly lower weight gain and diet intake compared to SH-CD (P < 0.05). The sham-operated animals received an average esophagitis score of 0.1 ± 0.1; this increased significantly in EDA-CD animals to 1.8 ± 0.14 (P < 0.001 versus SH-CD) and in EDA-BRB group to 1.7 ± 0.06 (P < 0.001 versus SH-CD), with BE changes also present. However, dietary supplementation of BRB did not alter or ameliorate the grade of esophagitis or the induction of BE. BRB diet caused a 43% increase in MnSOD levels compared to EDA-CD (0.73 ± 0.16; P = 0.09); however, this effect was not statistically significant and at 4 wk, EDA-CD (0.58 ± 0.12) showed an increase in MnSOD expression compared to SH-CD (0.34 ± 0.01). CONCLUSIONS: In conclusion, our data suggest that dietary BRB does not increase the levels of cellular antioxidant enzymes or reduce the levels of lipid peroxidation compared to a control diet, in a short-term study of gastroesophageal reflux induction in the EDA animal model. However, it remains to be tested whether this is indicative of its ineffectiveness to inhibit reflux-induced EAC incidence over the long term.