BACKGROUND: Psoriasis is a chronic inflammatory disease. In the treatment of psoriasis, cyclosporine is commonly prescribed systemic agents. However, long-term use of cyclosporine is not recommended because of side effects such as nephrotoxicity or hypertension. OBJECTIVE: To ascertain the improved safety of rotational therapy using cyclosporine and methotrexate, we investigated the frequency of abnormal results in laboratory test after long term rotational therapy using cyclosporine and methotrexate. METHODS: From January 2009 to June 2014, patients who were treated with cyclosporine or methotrexate were enrolled. The clinical data and usage of medications were reviewed. Laboratory tests were conducted before starting the treatment and regularly follow-up. The occurrences of any laboratory abnormalities during the treatments were investigated. RESULTS: A total of 21 psoriatic patients were enrolled. The mean of medication period and cumulative dose of cyclosporine and methotrexate were 497.81±512.06 days and 115.68±184.34 g in cyclosporine and 264.19±264.71 days and 448.71±448.63 mg in methotrexate. Laboratory abnormalities were found in total two patients after rotational therapy: two patients (9.5%) in aspartate aminotransferase/alanine aminotransferase and one patient (4.8%) in uric acid. No laboratory abnormalities were found in renal function test. CONCLUSION: We found that the rotational approaches using cyclosporine and methotrexate reduced the possibility of the development of nephrotoxicity. In addition to other advantage such as quick switching from one agent to another, the rotational therapy using cyclosporine and methotrexate can minimize the adverse events during the systemic treatment of chronic plaque psoriasis.
Aspartic Acid ; Clinical Chemistry Tests ; Combined Modality Therapy ; Cyclosporine* ; Follow-Up Studies ; Humans ; Hypertension ; Methotrexate* ; Psoriasis* ; Uric Acid

BACKGROUND: Psoriasis is a chronic inflammatory disease. In the treatment of psoriasis, cyclosporine is commonly prescribed systemic agents. However, long-term use of cyclosporine is not recommended because of side effects such as nephrotoxicity or hypertension. OBJECTIVE: To ascertain the improved safety of rotational therapy using cyclosporine and methotrexate, we investigated the frequency of abnormal results in laboratory test after long term rotational therapy using cyclosporine and methotrexate. METHODS: From January 2009 to June 2014, patients who were treated with cyclosporine or methotrexate were enrolled. The clinical data and usage of medications were reviewed. Laboratory tests were conducted before starting the treatment and regularly follow-up. The occurrences of any laboratory abnormalities during the treatments were investigated. RESULTS: A total of 21 psoriatic patients were enrolled. The mean of medication period and cumulative dose of cyclosporine and methotrexate were 497.81±512.06 days and 115.68±184.34 g in cyclosporine and 264.19±264.71 days and 448.71±448.63 mg in methotrexate. Laboratory abnormalities were found in total two patients after rotational therapy: two patients (9.5%) in aspartate aminotransferase/alanine aminotransferase and one patient (4.8%) in uric acid. No laboratory abnormalities were found in renal function test. CONCLUSION: We found that the rotational approaches using cyclosporine and methotrexate reduced the possibility of the development of nephrotoxicity. In addition to other advantage such as quick switching from one agent to another, the rotational therapy using cyclosporine and methotrexate can minimize the adverse events during the systemic treatment of chronic plaque psoriasis.
Aspartic Acid ; Clinical Chemistry Tests ; Combined Modality Therapy ; Cyclosporine* ; Follow-Up Studies ; Humans ; Hypertension ; Methotrexate* ; Psoriasis* ; Uric Acid

Autophagy is an evolutionarily conserved cellular process which degrades intracellular contents. The Atg17-Atg31-Atg29 complex plays a key role in autophagy induction by various stimuli. In yeast, autophagy occurs with autophagosome formation at a special site near the vacuole named the pre-autophagosomal structure (PAS). The Atg17-Atg31-Atg29 complex forms a scaffold for PAS organization, and recruits other autophagy-related (Atg) proteins to the PAS. Here, we show that Atg31 is a phosphorylated protein. The phosphorylation sites on Atg31 were identified by mass spectrometry. Analysis of mutants in which the phosphorylated amino acids were replaced by alanine, either individually or in various combinations, identified S174 as the functional phosphorylation site. An S174A mutant showed a similar degree of autophagy impairment as an Atg31 deletion mutant. S174 phosphorylation is required for autophagy induced by various autophagy stimuli such as nitrogen starvation and rapamycin treatment. Mass spectrometry analysis showed that S174 is phosphorylated constitutively, and expression of a phosphorylation-mimic mutant (S174D) in the Atg31 deletion strain restores autophagy. In the S174A mutant, Atg9-positive vesicles accumulate at the PAS. Thus, S174 phosphorylation is required for formation of autophagosomes, possibly by facilitating the recycling of Atg9 from the PAS. Our data demonstrate the role of phosphorylation of Atg31 in autophagy.
Alanine ; chemistry ; metabolism ; Amino Acid Motifs ; Aspartic Acid ; chemistry ; metabolism ; Autophagy ; genetics ; Autophagy-Related Proteins ; Carrier Proteins ; chemistry ; metabolism ; Gene Expression Regulation, Fungal ; Membrane Proteins ; chemistry ; metabolism ; Models, Molecular ; Molecular Sequence Data ; Nitrogen ; deficiency ; Phagosomes ; chemistry ; drug effects ; metabolism ; Phosphorylation ; Protein Transport ; Saccharomyces cerevisiae ; drug effects ; genetics ; metabolism ; Saccharomyces cerevisiae Proteins ; chemistry ; genetics ; metabolism ; Serine ; chemistry ; metabolism ; Signal Transduction ; Sirolimus ; pharmacology

Water soluble extract (WSE) is an important index for the quality evaluation of Astragali Radix (AR). In this study, the WSE of the wild AR from Shanxi province (SX) and the cultivated AR from Gansu Province (GS) were compared. The WSEs of two types of AR were determined according to the appendix of Chinese pharmacopoeia. Then the WSEs were subjected to NMR analysis, and the obtained data were analyzed using HCA, PCA, OPLS-DA, microarray analysis, and Spearman rank analysis. In addition, the Pearson correlation of differential metabolites were also calculated. The results showed that the WSE content of GS-AR (37.80%) was higher than that of SX-AR (32.13%). The main constituent of WSE was sucrose, and other 18 compounds, including amino acids, organic acids, were also detected. Multivariate analysis revealed that SX-AR contained more choline, succinic acid, citric acid, glutamate, taurine and aspartate, while GS samples contained more sucrose, arginine and fumaric acid. In addition, the Pearson correlations between different metabolites of the two types of AR also showed apparent differences. The results suggested that the WSE of two types of AR differs not only in the content, but also in the chemical compositions. Thus, the cultivation way is important to the quality of AR. This study supplied a new method for the comparison of extract of herbal drugs.
Arginine ; analysis ; Aspartic Acid ; analysis ; Choline ; analysis ; Citric Acid ; analysis ; Drugs, Chinese Herbal ; analysis ; chemistry ; Fumarates ; analysis ; Glutamic Acid ; analysis ; Magnetic Resonance Spectroscopy ; Multivariate Analysis ; Phylogeography ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; Succinic Acid ; analysis ; Sucrose ; analysis ; Taurine ; analysis

The purpose of this study is to explore depression metabolic markers in rat hippocampus and to investigate the anti-depressant effect of genipin and its mechanisms using nuclear magnetic resonance (NMR) metabonomics. Chronic unpredictable mild stress (CUMS) procedure was conducted to establish the depressive rat model. At the beginning of the third week, genipin low dose (25 mg x kg(-1)), middle dose (50 mg x kg(-1)), high dose (100 mg x kg(-1)), and venlafaxine (50 mg x kg(-1)) were given to the CUMS rats separately once daily for two weeks except control and model groups. Rat hippocampus was analyzed by 1H NMR based metabonomics after drug administration for 2 weeks. Significant differences in the metabolic profile of rat hippocampus of the CUMS treated group and the control group were observed with metabolic effects of CUMS including decreasing in glycine and N-acetylaspartate, increasing in inositol, glutamate, lactate, glutamine, taurine and alanine. Genipin showed ideal antidepressive effects at a dose of 50 mg x kg(-1) in rats, decrease of inositol, glutamate, lactate, alanine were observed, while glycine and N-acetylaspartate were increased. Important influence has been found on normal nervous system function of these significant changed metabolites, which suggests that the antidepressant effect of genipin may be played by enhancing the activity of neurons in hippocampus, repairing and improving the function of the neuron. The metabonomics approach is an effective tool for the investigation of the anti-depressant effect and pharmacologic mechanisms of genipin.
Alanine ; metabolism ; Animals ; Antidepressive Agents ; isolation & purification ; pharmacology ; Aspartic Acid ; analogs & derivatives ; metabolism ; Behavior, Animal ; drug effects ; Chronic Disease ; Depression ; drug therapy ; metabolism ; physiopathology ; Gardenia ; chemistry ; Glutamic Acid ; metabolism ; Glycine ; metabolism ; Hippocampus ; drug effects ; metabolism ; Inositol ; metabolism ; Iridoids ; isolation & purification ; pharmacology ; Lactic Acid ; metabolism ; Magnetic Resonance Spectroscopy ; Male ; Metabolomics ; Plants, Medicinal ; chemistry ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effects of exogenous hydrogen sulfide (H2S) on β-site APP cleaving enzyme 1 (BACE-1) and β-amyloid peptide (Aβ) metabolism in primary culture of neurons under high-glucose condition.

METHODSThe cortical neurons in primary culture under normal and high glucose (60 mmol/L) conditions for 24 h were exposed to 25, 50 and 100 µmol/L NaHS. Aβ1-42 concentration in the cell culture was measured by ELISA, and BACE-1 mRNA and protein levels were detected by fluorescent quantitative real-time PCR and Western blotting, respectively.

RESULTSCompared with the neurons cultured in normal glucose, the neurons exposed to high glucose showed significantly increased Aβ1-42 concentration and BACE-1 mRNA and protein expressions (P<0.05). Exposure to 25, 50 and 100 µmol/L NaHS significantly decreased Aβ1-42 concentration and BACE-1 mRNA and protein expressions in the high-glucose cell culture (P<0.05).

CONCLUSIONNeurons exposed to high glucose exhibit increased Aβ1-42 levels and BACE-1 mRNA and protein expressions, which can be concentration-dependently decreased by NaHS.

Amyloid Precursor Protein Secretases ; metabolism ; Amyloid beta-Peptides ; metabolism ; Animals ; Aspartic Acid Endopeptidases ; metabolism ; Cells, Cultured ; Culture Media ; chemistry ; Glucose ; chemistry ; Hydrogen Sulfide ; pharmacology ; Neurons ; drug effects ; metabolism ; Peptide Fragments ; metabolism ; Rats ; Rats, Sprague-Dawley

The aim of this paper is to compare the cytotoxicity and cellular uptake efficiency of three kinds of poly(b-benzyl-L-amino) block-poly(ethylene glycol) nanoparticles (PXA-PEG-NPs) using Calu-3 cells, and select one as a nasal drug delivery vector for curcumin (Cur). Poly(gamma-benzyl-L-glutamate) block-poly(ethylene glycol) nanoparticles (PBLG-PEG-NPs), poly(gamma-benzyl-L-lysine) block-poly(ethyleneglycol) nanoparticles (PZLL-PEG-NPs) and poly(gamma-benzyl-L-aspartate) block-poly(ethylene glycol) nanoparticles (PBLA-PEG-NPs) were prepared by emulsion-solvent evaporation method. MTT assays were used to evaluate the cytotoxicity of PXA-PEG-NPs against Calu-3 cells. The cellular uptake of nanoparticles was visualized by an inverted fluorescence microscope and quantified by a flow cytometer. The results indicated that even at high concentration of 2 mg x mL(-1) the three nanoparticles had no cytotoxicity on Calu-3 cells. Compared to the curcumin solution, the three curcumin-loaded PXA-PEG-NPs showed significantly higher cellular uptake efficiency on Calu-3 cells (at equal concentration of curcumin with 5 microg x mL(-1) Cur solution), PBLG-PEG-NPs group was the highest. The cellular uptake increased with incubation time, and has positive correlation with nanoparticle concentration. In brief, PXA-PEG-NPs are conducive to delivery Cur into cells, and PBLG-PEG-NPs might be provided as a good nasal drug delivery carrier.
Adenocarcinoma ; metabolism ; pathology ; Administration, Intranasal ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; metabolism ; Aspartic Acid ; chemistry ; toxicity ; Cell Line, Tumor ; Cell Survival ; drug effects ; Curcumin ; administration & dosage ; metabolism ; Drug Carriers ; Ethylene Glycol ; chemistry ; toxicity ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Lysine ; chemistry ; toxicity ; Nanoparticles ; Particle Size ; Polyethylene Glycols ; chemistry ; toxicity ; Polyglutamic Acid ; analogs & derivatives ; chemistry ; toxicity

This paper was aimed to study conserved motifs of voltage sensing proteins (VSPs) and establish a voltage sensing model. All VSPs were collected from the Uniprot database using a comprehensive keyword search followed by manual curation, and the results indicated that there are only two types of known VSPs, voltage gated ion channels and voltage dependent phosphatases. All the VSPs have a common domain of four helical transmembrane segments (TMS, S1-S4), which constitute the voltage sensing module of the VSPs. The S1 segment was shown to be responsible for membrane targeting and insertion of these proteins, while S2-S4 segments, which can sense membrane potential, for protein properties. Conserved motifs/residues and their functional significance of each TMS were identified using profile-to-profile sequence alignments. Conserved motifs in these four segments are strikingly similar for all VSPs, especially, the conserved motif [RK]-X(2)-R-X(2)-R-X(2)-[RK] was presented in all the S4 segments, with positively charged arginine (R) alternating with two hydrophobic or uncharged residues. Movement of these arginines across the membrane electric field is the core mechanism by which the VSPs detect changes in membrane potential. The negatively charged aspartate (D) in the S3 segment is universally conserved in all the VSPs, suggesting that the aspartate residue may be involved in voltage sensing properties of VSPs as well as the electrostatic interactions with the positively charged residues in the S4 segment, which may enhance the thermodynamic stability of the S4 segments in plasma membrane.
Arginine ; chemistry ; Aspartic Acid ; chemistry ; Cell Membrane ; physiology ; Conserved Sequence ; Ion Channel Gating ; Ion Channels ; chemistry ; Membrane Potentials ; Protein Structure, Tertiary

Alzheimer's disease (AD) is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide. Drug discovery for Alzheimer's disease therapy has been a hot research area and a big challenge, in which development of acetylcholinesterase (AChE) inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already. However, practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects. Thus, it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects. Based on the accurate crystallographic studies about AChE, strategies for multi-binding site AChE inhibitors have been formed, followed by design of the multi-target directed ligands. In this review, the structures and binding modes of commercial AChE inhibitors were briefly discussed, together with the development of AChE inhibitor design for AD therapy: from multi-binding site inhibitors to multi-target directed ligands.
Acetylcholinesterase ; chemistry ; metabolism ; Alzheimer Disease ; drug therapy ; Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Amyloid beta-Peptides ; metabolism ; Animals ; Aspartic Acid Endopeptidases ; antagonists & inhibitors ; Binding Sites ; Butyrylcholinesterase ; chemistry ; metabolism ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Drug Design ; Humans ; Ligands ; Monoamine Oxidase Inhibitors ; chemical synthesis ; chemistry ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Structure-Activity Relationship

OBJECTIVE: To examine the changes of metabolites in the bilateral thalamus of patients with secondarily generalized tonic-clonic seizure (SGTCS) and to explore the mechanism of SGTCS. METHODS: Thirty patients with SGTCS (epilepsy group) and 30 matched healthy controls (control group) were examined by 1H-magnetic resonance spectroscopy (1H-MRS). The levels of N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine phosphocreatine (Cr-PCr), and myo-inositol (mI) of the bilateral thalamus were measured in both the epilepsy group and the control group. The ratios of NAA/Cr-PCr, NAA/(Cr-PCr+Cho), Cho/Cr-PCr and mI/Cr-PCr were compared and analyzed in the 2 groups. RESULTS: The ratios of NAA/Cr-PCr, and NAA/(Cr-PCr+Cho)(1.7074 ± 0.2214; 0.9333 ± 0.2173) in the left thalamus in the epilepsy group were significantly lower than those in the control group(1.8834 ±0.2093; 1.1243 ±0.2447)(P<0.05). The ratios of NAA/Cr-PCr, and NAA/(Cr- PCr+Cho) (1.7472 ±0.2439; 0.9165 ±0.2462) in the right thalamus in the epilepsy group were also significantly lower than those in the control group(1.8925 ± 0.2004; 1.0941 ± 0.2372)(P<0.05). There were no significant differences in the ratios of NAA/Cr-PCr, NAA/(Cr-PCr+Cho), Cho/Cr- PCr, and mI/Cr-PCr between the bilateral thalamis in the epilepsy group (P>0.05). CONCLUSION There is neuronal dysfunction in the bilateral thalamus in the epilepsy group. Abnormal changes of the bilateral thalamus are involved in the mechanism of SGTCS.
Adolescent ; Adult ; Aspartic Acid ; analogs & derivatives ; analysis ; Brain Chemistry ; Case-Control Studies ; Choline ; analysis ; Energy Metabolism ; physiology ; Epilepsy, Generalized ; metabolism ; physiopathology ; Epilepsy, Tonic-Clonic ; metabolism ; physiopathology ; Female ; Humans ; Magnetic Resonance Spectroscopy ; methods ; Male ; Middle Aged ; Thalamus ; metabolism ; physiopathology ; Young Adult