Silymarin pretreatment protects against ethanol-induced memory impairment: Biochemical and histopathological evidence.

BACKGROUND: Ethanol (Eth.) abuse induces memory impairment. Oxidative damage and apoptosis are considered the likely causes of memory impairment. Silymarin (Sil.) is a flavonoid isolated from the plant Silymarin marianum (milk thistle). While studies have reported the neuroprotective effect of Sil. against neurodegenerative processes, the precise mechanism of action of Sil. in Eth.-induced memory impairment remains unclear. METHODS: Twenty-eight rats were equally divided into four groups: Control (saline 1 ml/rat); Sil. (200 mg/kg for 30 days); Eth. (2 g/kg/day for 30 days); and Sil. + Eth. Behavioral tests including inhibitory avoidance and open field were used to investigate memory and locomotion. Brain antioxidant parameters, including catalase, superoxide dismutase, total antioxidant capacity and total thiol group, plus oxidative parameters, including malondialdehyde and total oxidant status, followed by hippocampal apoptosis (Bax/Bcl2, cleaved caspase) and histopathological changes were evaluated in the groups. RESULTS: While the administration of Eth. impaired memory, Sil. significantly reversed Eth-induced memory deficits. Eth. administration also augmented brain oxidative and hippocampal apoptosis parameters. In contrast, a marked reduction in brain antioxidant and anti-apoptotic parameters was observed in the Eth. group. At the tissue level, hippocampal sections from Eth.-treated animals revealed severe neuronal damage. The administration of Sil. to Eth.-treated rats remarkably alleviated all the said Eth.-induced biochemical and histopathological effects. On the contrary, Sil. alone did not change the behavior and biochemical/molecular parameters. CONCLUSION: The memory-enhancing effect of Sil. in Eth.-induced demented rats may be partly mediated by the augmented antioxidant effects and amelioration of apoptotic and histopathological changes.

An Open-Label Pilot Study to Evaluate the Efficacy of Tofacitinib in Moderate to Severe Patch-Type Alopecia Areata, Totalis, and Universalis.

Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of ∼2%. In AA, the immune system targets the hair follicle, resulting in clinical hair loss. The prognosis of AA is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Because these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors. In preclinical trials in mice, tofacitinib successfully prevented AA development and reversed established disease. In our tofacitinib trial in 12 patients with moderate to severe AA, 11 patients completed a full course of treatment with minimal adverse events. Following limited response to the initial dose (5 mg b.i.d.), the dose was escalated (10 mg b.i.d.) for nonresponding subjects. Eight of 12 patients demonstrated ≥50% hair regrowth, while three patients demonstrated <50% hair regrowth, as measured by Severity in Alopecia Tool scoring. One patient demonstrated no regrowth. Gene expression profiles and Alopecia Areata Disease Activity Index scores correlated with clinical response. Our open-label studies of ruxolitinib and tofacitinib have shown dramatic clinical responses in moderate to severe AA, providing strong rationale for larger clinical trials using JAK inhibitors in AA. ClinicalTrials.gov ID NCT02299297.

Role of the immune system and immunological circuits in psoriasis.

Psoriasis vulgaris is a chronic skin disease in which our understanding of the pathogenesis has substantially grown in recent years. Our current appreciation of the role of the immune system is that it plays a necessary and driving role in the disease process. Investigations into the genetics of psoriasis has spurred further examinations into the contributions of immune mediators such as IL-23, IL-17, IL-22, and TNF as well as cellular mediators including a variety of dendritic cell populations of the skin and the growing number of T cell types, including the Th17 and Th22 subsets. Investigations into how these soluble and cellular elements interact with each other and the skin and form complex signal circuits to engender the psoriasis phenotype is starting to become elucidated. Furthermore, these recent advances have been fruitful in leading to the development of new classes of biologic therapeutics that are remarkably effective in halting the disease process.

Fine steps of electrocatalytic oxidation and sensitive detection of some amino acids on copper nanoparticles.

The electrocatalytic oxidation of five amino acids-glycine, aspartic acid, cysteine, glutamic acid, and tyrosine-on two copper-based electrodes comprising copper microparticle-modified carbon paste electrode (m-CPE) and copper nanoparticle-modified CPE (n-CPE) was investigated. In the voltammograms recorded using m-CPE, a single anodic peak related to the oxidation of amino acids appeared and was related to the electrocatalytic oxidation of the amino acids via the electrogenerated Cu(III) species. Using n-CPE, however, two overlapped anodic peaks in the voltammograms appeared and were related to two fine tunable steps of the oxidation process. The currents of the two peaks were controlled by diffusion and were confirmed by chronoamperometric measurements. The amino acids were oxidized on n-CPE at higher rates and at lower potentials compared with m-CPE. This was attributed to the nanosize of copper nanoparticles. Some primary linear-chain amines and primary branched-chain amines were oxidized on the copper-based electrodes as markers. The catalytic rate constants, the transfer coefficients, and the diffusion coefficients for the amino acids are reported. Simple, sensitive, and time-saving sensing procedures in both batch and flow systems were developed for the analysis of the amino acids, and the corresponding analytical parameters are reported.

Electrocatalytic oxidation and determination of deferasirox and deferiprone on a nickel oxyhydroxide-modified electrode.

The electrocatalytic oxidation of two orally administered iron chelator drugs (deferiprone, CP20, and deferasirox, ICL670) was investigated on a nickel oxyhydroxide-modified nickel electrode in alkaline solution. The oxidation process involved and its kinetics were investigated using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques, as well as steady-state polarization measurements. Voltammetric studies indicated that in the presence of the drugs under study, the anodic peak current of low-valence nickel species increased, followed by a decrease in the corresponding cathodic current. This result indicates that the drugs were oxidized via oxyhydroxide species immobilized on the electrode surface via an EC' mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by the drugs in question was also investigated. The corresponding rate law under the control of charge transfer was developed, and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of the drugs and the electron-transfer coefficients are reported. A sensitive, simple, and time-saving amperometric procedure was developed for the analysis of deferasirox and deferiprone, with detection limits of 28 and 19 microM, respectively. The electrode was used for the direct assay of deferasirox and deferiprone tablets.