Effects of subthalamic nucleus deep brain stimulation on quality of life and motor and depressive symptoms in Parkinson's disease

AbstractThe objective of this paper is to review the available literature concerning the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on quality of life (QoL) and motor and depressive symptoms in patients with Parkinson's disease (PD). These studies demonstrate that STN-DBS has an effect on QoL and symptoms in patients with PD. There was a significant improvement in QoL following STN-DBS compared with no improvement after medical therapy. PD patients treated with STN-DBS had a 40–50% improvement in motor function. Nevertheless, depressive symptoms did not reveal consistent change

CHITINASE LIKE1 Regulates Root Development of Dark-Grown Seedlings by Modulating Ethylene Biosynthesis in Arabidopsis thaliana

The plant hormone ethylene plays a regulatory role in development in light- and dark-grown seedlings. We previously isolated a group of small-molecule compounds with a quinazolinone backbone, which were named acsinones (for ACC synthase inhibitor quinazolinones), that act as uncompetitive inhibitors of 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS). Thus, the triple response phenotype, which consists of shortened hypocotyls and roots, radial swelling of hypocotyls and exaggerated curvature of apical hooks, was suppressed by acsinones in dark-grown (etiolated) ethylene overproducer (eto) seedlings. Here, we describe our isolation and characterization of an Arabidopsis revert to eto1 9 (ret9) mutant, which showed reduced sensitivity to acsinones in etiolated eto1 seedlings. Map-based cloning of RET9 revealed an amino acid substitution in CHITINASE LIKE1 (CTL1), which is required for cell wall biogenesis and stress resistance in Arabidopsis. Etiolated seedlings of ctl1ret9 showed short hypocotyls and roots, which were augmented in combination with eto1-4. Consistently, ctl1ret9 seedlings showed enhanced sensitivity to exogenous ACC to suppress primary root elongation as compared with the wild type. After introducing ctl1ret9 to mutants completely insensitive to ethylene, genetic analysis indicated that an intact ethylene response pathway is essential for the alterations in root and apical hook but not hypocotyl in etiolated ctl1ret9 seedlings. Furthermore, a mild yet significantly increased ethylene level in ctl1 mutants was related to elevated mRNA level and activity of ACC oxidase (ACO). Moreover, genes associated with ethylene biosynthesis (ACO1 and ACO2) and response (ERF1 and EDF1) were upregulated in etiolated ctl1ret9 seedlings. By characterizing a new recessive allele of CTL1, we reveal that CTL1 negatively regulates ACO activity and the ethylene response, which thus contributes to understanding a role for ethylene in root elongation in response to perturbed cell wall integrity

Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.

PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention

Metabolism and Pharmacokinetics of San-Huang-Xie-Xin-Tang, a Polyphenol-Rich Chinese Medicine Formula, in Rats and Ex-Vivo Antioxidant Activity

San-Huang-Xie-Xin-Tang (SHXXT), a widely used Chinese herbal formula, consists of rhizomes of Rheum officinale, roots of Scutellaria baicalensis and rhizomes of Coptis chinesis. This study investigated the metabolism and pharmacokinetics of polyphenols in SHXXT, including baicalin, baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol. The quantitation methods of SHXXT decoction and rat serum using high performance liquid chromatography were developed and validated in this study. After oral administration of SHXXT decoction to rats, the parent forms of various constituents and their conjugated metabolites in serum were determined before and after hydrolysis with β-glucuronidase and sulfatase. The results showed that only free form of rhein can be quantitated, whereas the parent forms of coptisine, palmatine, berberine, baicalein, wogonin, emodin, aloe-emodin and chrysophanol were not detected in serum. The glucuronides of baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol were the predominant forms in bloodstream. In order to evaluate the in vivo antioxidant activity of SHXXT, the serum metabolite of SHXXT was prepared, characterized and followed by evaluation of the effect on AAPH-induced hemolysis. The results indicated that metabolites of SHXXT exhibited significant free radical scavenging activity. We suggest that biologists redirect their focus to the bioactivity of the conjugated metabolites of these polyphenols

Metabolism and Pharmacokinetics of San-Huang-Xie-Xin-Tang, a Polyphenol-Rich Chinese Medicine Formula, in Rats and Ex-Vivo Antioxidant Activity

San-Huang-Xie-Xin-Tang (SHXXT), a widely used Chinese herbal formula, consists of rhizomes of Rheum officinale, roots of Scutellaria baicalensis and rhizomes of Coptis chinesis. This study investigated the metabolism and pharmacokinetics of polyphenols in SHXXT, including baicalin, baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol. The quantitation methods of SHXXT decoction and rat serum using high performance liquid chromatography were developed and validated in this study. After oral administration of SHXXT decoction to rats, the parent forms of various constituents and their conjugated metabolites in serum were determined before and after hydrolysis with β-glucuronidase and sulfatase. The results showed that only free form of rhein can be quantitated, whereas the parent forms of coptisine, palmatine, berberine, baicalein, wogonin, emodin, aloe-emodin and chrysophanol were not detected in serum. The glucuronides of baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol were the predominant forms in bloodstream. In order to evaluate the in vivo antioxidant activity of SHXXT, the serum metabolite of SHXXT was prepared, characterized and followed by evaluation of the effect on AAPH-induced hemolysis. The results indicated that metabolites of SHXXT exhibited significant free radical scavenging activity. We suggest that biologists redirect their focus to the bioactivity of the conjugated metabolites of these polyphenols

Improving thermal stability and efficacy of BCNU in treating glioma cells using PAA-functionalized graphene oxide

Yu-Jen Lu1,2,#, Hung-Wei Yang1,#, Sheng-Che Hung3, Chiung-Yin Huang2, Shin-Ming Li4, Chen-Chi M Ma4, Pin-Yuan Chen2, Hong-Chieh Tsai2, Kuo-Chen Wei2, Jyh-Ping Chen1 1Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan, Taiwan; 2Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan, Taiwan; 3Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan#These authors contributed equally to this workBackground: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commercial chemotherapeutic drug for treating malignant brain tumors, has poor thermal stability and a short half-life. Immobilization of BCNU on a nanocarrier might increase the thermal stability of BCNU and extend its half-life.Methods: Nanosized graphene oxide (GO) could be modified by polyacrylic acid (PAA) to improve the aqueous solubility and increase the cell penetration efficacy of the nanocarrier. PAA–GO intended as a drug carrier for BCNU was prepared and characterized in this study. The size and thickness of PAA–GO was investigated by transmission electron microscopy and atomic force microscopy, and the presence of PAA functional groups was confirmed by electron spectroscopy for chemical analysis and thermogravimetric analysis. BCNU was conjugated to PAA–GO by covalent binding for specific killing of cancer cells, which could also enhance the thermal stability of the drug.Results: Single layer PAA–GO (about 1.9 nm) with a lateral width as small as 36 nm was successfully prepared. The optimum drug immobilization condition was by reacting 0.5 mg PAA–GO with 0.4 mg BCNU, and the drug-loading capacity and residual drug activity were 198 µg BCNU/mg PAA–GO and 70%, respectively. This nanocarrier significantly prolonged the half-life of bound BCNU from 19 to 43 hours compared with free drug and showed efficient intracellular uptake by GL261 cancer cells. The in vitro anticancer efficacy of PAA–GO–BCNU was demonstrated by a 30% increase in DNA interstrand cross-linking and a 77% decrease in the IC50 value toward GL261 compared with the same dosage of free drug.Conclusion: Nanosized PAA–GO serves as an efficient BCNU nanocarrier by covalent binding. This nanocarrier will be a promising new vehicle for an advanced drug delivery system in cancer therapy.Keywords: graphene oxide, BCNU, glioma cells, drug delivery, thermal stabilit