Effect of pharmacogenomic testing on the clinical treatment of patients with depressive disorder: A randomized clinical trial.

BACKGROUND: Pharmacotherapy is one of the primary treatment modalities for depression. However, there is considerable variability in the individual response to antidepressant medications. Personalized medicine guided by pharmacogenomic testing may hold promise in addressing this issue. METHODS: In this study, 665 depressive patients were randomly enrolled into two groups: the pharmacogenomic testing group (n = 333) and the control group (n = 332). In the testing group, participants underwent pharmacogenomic testing, and clinicians customized the treatment plan with the result, while the control group relied solely on clinicians' experience. The primary outcomes were the proportion of remission and response, assessed with Hamilton Depression Rating Scale (HDRS). The secondary outcomes included changes in HDRS scores over time and frequency of adverse drug reactions by the participants. RESULTS: At week 8, the pharmacogenomic testing group showed significantly higher remission rates (24.0 % v.s. 15.1 %; RR = 1.117; P = 0.007) and response rates (39.3 % v.s. 25.7 %; RR = 1.225; P < 0.001) compared to the control group. By week 12, the pharmacogenomic testing group continued to demonstrate significant advantages in remission (31.0 % v.s. 20.0 %; RR = 1.159; P = 0.003) and response (48.7 % v.s. 37.3 %; RR = 1.224; P = 0.006). Additionally, adverse drug reactions were less frequent in the pharmacogenomic testing group. LIMITATIONS: This study is not blind to clinicians and it's a single-center study. CONCLUSIONS: Pharmacogenomic testing-guided drug therapy can provide greater assistance in the treatment of depression.

Divergence in the distribution of di(2-ethylhexyl) phthalate (DEHP) in two soils.

Understanding the distribution of di(2-ethylhexyl) phthalate (DEHP) is necessary for future risk evaluation of DEHP in agricultural soils. This study used 14C-labeled DEHP to examine its volatilization, mineralization, extractable residues, and non-extractable residues (NERs) incubated in Chinese typical red and black soil with/without Brassica chinensis L. Results showed that after incubated for 60 days, 46.3% and 95.4% of DEHP were mineralized or transformed into NERs in red and black soil, respectively. The distribution of DEHP in humic substances as NER descended in order: humin > fulvic acids > humic acids. DEHP in black soil was more bioavailable, with 6.8% of initial applied radioactivity left as extractable residues at the end of incubation when compared with red soil (54.5%). Planting restrained the mineralization of DEHP by 18.5% and promoted the extractable residues of DEHP by 1.5% for black soil, but no such restrain was observed in red soil. These findings provide valuable information for understanding the distribution of DEHP in different soils and develop the understanding for the risk assessments of PAEs in typical soils.

Joint effects of CuO nanoparticles and perfluorooctanoic acid on cabbage (Brassica pekinensis L.).

Coexisting nanoparticles (NPs) may change plant accumulation and toxicity of perfluorooctanoic acid (PFOA) in soil, but research is very scarce. In this study, cabbage (Brassica pekinensis L.) was exposed to single or combined treatments of PFOA (2 mg/kg and 4 mg/kg) and copper oxide NPs (nCuO, 200 mg/kg and 400 mg/kg) for 40 days. At harvest, biomass, photosynthesis index, and nutrient composition of cabbage, as well as plant accumulation of PFOA and Cu, were measured. Results showed that nCuO and PFOA were adverse to cabbage growth by decreasing chlorophyll contents, inhibiting photosynthesis and transpiration, and interfering with the utilization of nutrient components. Besides, they also affected each other's plant utilization and transmission. Especially, nCuO at a high dose (400 mg/kg) significantly increased the transport of coexisting PFOA (4 mg/kg) content (by 124.9% and 118.2%) to cabbage shoots. The interaction mechanism between nCuO and PFOA is unknown, and more research is needed to evaluate their composite phytotoxicity.

A Novel Fluoro-Pyrazine-Bridged Donor-Accepter-Donor Fluorescent Probe for Lipid Droplet-Specific Imaging in Diverse Cells and Superoxide Anion Generation.

PURPOSE: Lipid droplets (LDs) are dynamic organelles which associated with many metabolic processes. Reliable long-term imaging of LD is of great importance in LD-based therapy and research. Conventional fluorescent probes suffer from poor photostability and difficulty of preparation, which compromise their LD imaging ability. In this study, we aim to provide a novel and universal fluorescent probe for LD-specific imaging in both eukaryotic and prokaryotic cells. The versatile and potential applications of the probe were also evaluated. METHODS: We used one-step Suzuki coupling reaction to synthesize a fluoro-pyrazine-bridged donor-acceptor-donor fluorescent probe (T-FP-T). The fluorescent properties and stability of T-FP-T were detected. Then, LD-specific imaging and dynamic movement tracking capabilities of T-FP-T were studied in fungus, bacteria, plant and animal tissues. The biosafety and photodynamic toxicity of the probe under different light irradiation were characterized. RESULTS: T-FP-T showed large Stokes shift, superior brightness, excellent photostability, low toxicity. T-FP-T exhibited significant overlaps with adipophilin antibody or the commercial LD probe (LipidSpot™) in the cytoplasm, but not with Mitotracker red, Lysotracker red and Peroxisome Labeling dye. Moreover, T-FP-T also showed efficient superoxide anion generation capability under white LED light irradiation. The viability of Hela cells co-treated with T-FP-T and 1-h white LED light irradiation decreased to 62%. CONCLUSIONS: All these outstanding capabilities make T-FP-T a new efficient LD-specific imaging probe. The generated superoxide anion from T-FP-T under white LED light irradiation could cause obvious cell death, which will inspire broad study in LD-targeted photodynamic therapy.

Novel Pyrazine-Bridged D-A-D Type Charge Neutral Probe for Membrane Permeable Long-Term Live Cell Imaging.

A novel donor-acceptor-donor (D-A-D) type compound containing pyrazine as the acceptor and triphenylamine as the donor has been designed and synthesized. The photophysical properties and biocompatibility of this probe, namely (OMeTPA)2-Pyr for live cell imaging were systematically investigated, with observed large Stokes shifts, high photostability, and low cytotoxicity. Furthermore, we demonstrated that (OMeTPA)2-Pyr could permeate live cell membranes for labeling. The proposed mechanism of this probe was the binding and shafting through membrane integral transport proteins by electrostatic and hydrophobic interactions. These salient and novel findings can facilitate the strategic design of new pyrazine-fused charge-neutral molecular platforms as fluorescent probes, for long-term in situ dynamic monitoring in live cells.

Design, synthesis and evaluation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential hypolipidemic and hepatoprotective agents.

Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice. Moreover, hepatic transaminases (AST and ALT) were obviously ameliorated after treatment with T1 and the histological observation indicated that T1 ameliorated the injury in liver tissue and inhibited the hepatic lipid accumulation. In the livers of T1-administrated rat, the levels of PPARα related to lipids metabolism were up-regulated. Additional effects such as antioxidant, anti-inflammatory and H2S releasing action confirmed and reinforced the activity of T1 as a potential multifunctional hypolipidemic and hepatoprotective agent.

Design, synthesis and evaluation of phenylfuroxan nitric oxide-donor phenols as potential anti-diabetic agents.

Both nitric oxide (NO) dysfunction and oxidative stress have been regarded as the important factors in the development and progression of diabetes and its complications. Multifunctional compounds with hypoglycemic, NO supplementation and anti-oxidation will be the promising agents for treatment of diabetes. In this study, six phenylfuroxan nitric oxide (NO) donor phenols were synthesized, which were designed via a combination approach with phenylfuroxan NO-donor and natural phenols. These novel synthetic compounds were screened in vitro for α-glucosidase inhibition, NO releasing, anti-oxidation, anti-glycation and anti-platelet aggregation activity as well as vasodilatation effects. The results exhibited that compound T5 displayed more excellent activity than other compounds. Moreover, T5 demonstrated significant hypoglycemic activity in diabetic mice and oral glucose tolerance test (OGTT) mice. T5 also showed NO releasing and anti-oxidation in diabetic mice. Based on these results, compound T5 deserves further study as potential new multifunctional anti-diabetic agent with antioxidant, NO releasing, anti-platelet aggregation and vasodilatation properties.

5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.

Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.

Synthesis, nitric oxide release, and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents.

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC50 value of 0.060 µM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.

A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects.

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (p < 0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.

Hydroxytyrosol nicotinate, a new multifunctional hypolipidemic and hypoglycemic agent.

Hydroxytyrosol (HT) is a natural polyphenol antioxidant that exists in olive oil. In the study of multifunctional hypolipidemic of nicotinic derivatives, we found that hydroxytyrosol nicotinate (HT-N) incorporation of niacin with HT displayed ?-glucosidase inhibitory activities in vitro, such as yeast ?-glucosidase (IC50?=?117.72??M) and rat intestinal ?-glucosidases maltase (IC50?=?31.86??M) and sucrase (IC50?=?22.99??M), and had a good control of postprandial blood glucose (PBG). HT-N shown significantly hypoglycemic action by 16.9% and protection of pancreatic tissue in type 2 diabetic mellitus (T2DM) mouse model. HT-N also shown a potent antioxidant activity and property of anti-glycation in vitro, which were benefit for ameliorating diabetic complications. Moreover, HT-N exhibited much significant hypolipidemia, lowering plasma triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 34.6%, 45.8% and 32.1% respectively, in hyperlipidemic mice induced by Triton WR 1339. The results indicated that HT-N has hypolipidemic, hypoglycemic and antioxidant actions. All these properties could be conducive to amelioration of oxidative stress, hyperlipidemia, and diabetes that HT-N may serve as a multifunctional potential therapeutic strategy in diabetic patients with hyperlipidemia.

A new multifunctional hydroxytyrosol-fenofibrate with antidiabetic, antihyperlipidemic, antioxidant and antiinflammatory action.

Dyslipidemia, oxidative stress and inflammation are major risky factors involved in the pathophysiology of type 2 diabetes mellitus and atherosclerosis. Multifunctional intervene is more meaningful. The aim of this study was to evaluate the multifunctional effects of two new compounds, combination of fenofibric acid (FA) with tyrosol (T) or hydroxytyrosol (HT). Compared with fenofibrate (FF), FF-HT exhibited excellent antioxidant capacities in vitro and much improved hypolipidemia, reducing plasma triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 76%, 54%, and 28%, while FF-T decreased the plasma parameters by 16%, 10%, and 20% in hyperlipidemic mice induced by Triton WR 1339. Furthermore, compound FF-HT exhibited significant antihyperglycemic, antihyperlipidemic, antioxidant and anti-inflammatory activities as well as attenuating hepatotoxicity in a type 2 diabetes experimental mouse model. The histological findings showed that FF-HT suppressed the development of hepatic lipid accumulation and ameliorated the damage in hepatic and pancreatic tissues compared to model mice. This study indicates for the first time that reasonable optimized drug design produce a compound entity which is conducive to the prevention of type 2 diabetes mellitus and its complications.