Since publishing our earlier report describing a strategy for the treatment of central nervous system (CNS) diseases by inhibiting the cell cycle and without disrupting neurogenesis (Liu et al. 2010), we now update and extend this strategy to applications in the treatment of cancers as well. Here, we put forth the concept of "aberrant cell cycle diseases" to include both cancer and CNS diseases, the two unrelated disease types on the surface, by focusing on a common mechanism in each aberrant cell cycle reentry. In this paper, we also summarize the pharmacological approaches that interfere with classical cell cycle molecules and mitogenic pathways to block the cell cycle of tumor cells (in treatment of cancer) as well as to block the cell cycle of neurons (in treatment of CNS diseases). Since cell cycle inhibition can also block proliferation of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits, we propose that future strategies aimed at cell cycle inhibition in treatment of aberrant cell cycle diseases (i.e., cancers or CNS diseases) should be designed with consideration of the important side effects on normal neurogenesis and cognition.

Heat shock proteins (Hsps) are induced by heat shock via heat shock factor proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types but is induced mainly in neurons in the ischemic penumbra. Overexpression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In the brain, protein kinase D phosphorylates Hsp27 following ischemia which then binds apoptosis signal-regulating kinase 1 to prevent MKK4/7, c-Jun NH(2)-terminal kinase, and Jun-induced apoptosis, and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion, and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant, both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic.

Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies.

Confinement of electrons can occur in metal islands or in continuous films grown heteroepitaxially upon a substrate of a different metal or on a metallic alloy. Associated quantum size effects (QSE) can produce a significant height-dependence of the surface free energy for nanoscale thicknesses of up to 10-20 layers. This may suffice to induce height selection during film growth. Scanning STM analysis has revealed remarkable flat-topped or mesa-like island and film morphologies in various systems. We discuss in detail observations of QSE and associated film growth behavior for Pb/Cu(111), Ag/Fe(100), and Cu/fcc-Fe/Cu(100) [A/B or A/B/A], and for Ag/NiAl(110) with brief comments offered for Fe/Cu₃Au(001) [A/BC binary alloys]. We also describe these issues for Ag/5-fold i-Al-Pd-Mn and Bi/5-fold i-Al-Cu-Fe [A/BCD ternary icosohedral quasicrystals]. Electronic structure theory analysis, either at the level of simple free electron gas models or more sophisticated Density Functional Theory calculations, can provide insight into the QSE-mediated thermodynamic driving force underlying height selection.

Aim: Our previous study demonstrated miR-122 mimic decreased NOS2 expression in blood leucocytes and improved stroke outcomes when given immediately after middle cerebral artery occlusion (MCAO) in rats. Since NOS2 is associated with neuro-inflammation in stroke and decreasing NOS2 expression alone in leucocytes is insufficient to improve stroke outcomes, we hypothesized that miR-122 mimic may also decrease NOS2 expression in brain microvascular endothelial cells (BMVECs) even at extended time windows. Methods: We administered PEG-liposome wrapped miR-122 mimic (2.4 mg/kg, i.v.) 0 or 6 h after MCAO, and assessed stroke volume and NOS2 expression in BMVECs 24 h following MCAO in rats. Luciferase reporter assays were used to determine if miR-122 binds to 3' untranslated regions (3'UTR) of NOS2. Results: The data showed that miR-122 mimic decreased infarct volumes and decreased MCAO-induced NOS2 over-expression in BMVECs. However, miR-122 did not bind to 3'UTR of NOS2 in the luciferase assays. Conclusion: The data show the 6-h period of therapeutic efficacy of miR-122 mimic which could relate to indirect knockdown of NOS2 in both BMVECs and leucocytes.

We describe here the characteristic features of the ringing we observed following large PMT signals in the Daya Bay reactor antineutrino experiment. We conclude that the ceramic capacitors used in the circuitry of the PMT bases and the HV-signal decouplers are the primary cause for this ringing. We present some possible schemes to reduce the ringing when replacing these ceramic capacitors is not feasible. © 2012 Chinese Physical Society and the Institute of High Energy Physics of the Chinese Academy of Sciences and the Institute of Modern Physics of the Chinese Academy of Sciences and IOP Publishing Ltd.

Background

Duchenne Muscular Dystrophy (DMD) is a recessive X-linked form of muscular dystrophy. Steroid therapy has clinical benefits for DMD patients, but the mechanism remains unclear.

Objective

This study was designed to identify mRNAs and microRNAs regulated in Duchenne Muscular Dystrophy patients prior to and after steroid therapy.

Methods

Genome wide transcriptome profiling of whole blood was performed to identify mRNAs and microRNAs regulated in DMD patients.

Results

The data show many regulated mRNAs and some microRNAs, including some muscle-specific microRNAs (e.g., miR-206), that were significantly altered in blood of young (age 3-10) DMD patients compared to young controls. A total of 95 microRNAs, but no mRNAs, were differentially expressed in older DMD patients compared to matched controls (age 11-20). Steroid treatment reversed expression patterns of several microRNAs (miR-206, miR-181a, miR-4538, miR-4539, miR-606, and miR-454) that were altered in the young DMD patients. As an example, the over-expression of miR-206 in young DMD patients is predicted to down-regulate a set of target genes (e.g., RHGAP31, KHSRP, CORO1B, PTBP1, C7orf58, DLG4, and KLF4) that would worsen motor function. Since steroids decreased miR-206 expression to control levels, this could provide one mechanism by which steroids improve motor function.

Conclusions

These identified microRNA-mRNA alterations will help better understand the pathophysiology of DMD and the response to steroid treatment.

Background

There is a growing realization that COPD, or at least emphysema, involves several processes presenting in aging and cellular senescence. Endothelial progenitor cells (EPCs) contribute to neovascularization and play an important role in the development of COPD. The gene for p16^Ink4a is a major dominant senescence one. The aim of the present study was to observe changes in lung function, histomorphology of lung tissue, and expression of p16^Ink4a in lung tissue and bone marrow-derived EPCs in emphysematous mice induced by cigarette-smoke extract (CSE), and further to search for a potential candidate agent protecting against emphysema induced by CSE.

Materials and methods

An animal emphysema model was induced by intraperitoneal injection of CSE. 5-Aza-2'-deoxycytidine (5-Aza-CdR) was administered to the emphysematous mice. Lung function and histomorphology of lung tissue were measured. The p16^Ink4a protein and mRNA in EPCs and lung tissues were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction, respectively.

Results

CSE induced emphysema with increased p16^Ink4a expression in lung tissue and bone marrow-derived EPCs. 5-Aza-CdR partly protected against emphysema, especially in the lung-morphology profile, and partly protest against the overexpression of p16^Ink4a in EPCs and lung tissue induced by CSE.

Conclusion

5-Aza-CdR partly protected against emphysema in mice via suppressing p16^Ink4a expression in EPCs and lung tissue.

Cancers and neurological disorders are two major types of diseases. We previously developed a new concept termed "Aberrant Cell Cycle Diseases" (ACCD), revealing that these two diseases share a common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncogene activation and tumor suppressor inactivation, which are hallmarks of both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase inhibition, tumor suppressor elevation) can be leveraged for neurological treatments. The United States Food and Drug Administration (US FDA) has so far approved 74 kinase inhibitors, with numerous other kinase inhibitors in clinical trials, mostly for the treatment of cancers. In contrast, there are dire unmet needs of FDA-approved drugs for neurological treatments, such as Alzheimer's disease (AD), intracerebral hemorrhage (ICH), ischemic stroke (IS), traumatic brain injury (TBI), and others. In this review, we list these 74 FDA-approved kinase-targeted drugs and identify those that have been reported in preclinical and/or clinical trials for neurological disorders, with a purpose of discussing the feasibility and applicability of leveraging these cancer drugs (FDA-approved kinase inhibitors) for neurological treatments.

Traumatic brain injury (TBI) is often associated with intracerebral and intraventricular hemorrhage. Thrombin is a neurotoxin generated at bleeding sites fater TBI and can lead to cell death and subsequent cognitive dysfunction via activation of Src family kinases (SFKs). We hypothesize that inhibiting SFKs can protect hippocampal neurons and improve cognitive memory function after TBI. To test these hypotheses, we show that moderate lateral fluid percussion (LFP) TBI in adult rats produces bleeding into the cerebrospinal fluid (CSF) in both lateral ventricles, which elevates oxyhemoglobin and thrombin levels in the CSF, activates the SFK family member Fyn, and increases Rho-kinase 1(ROCK1) expression. Systemic administration of the SFK inhibitor, PP2, immediately after moderate TBI blocks ROCK1 expression, protects hippocampal CA2/3 neurons, and improves spatial memory function. These data suggest the possibility that inhibiting SFKs after TBI might improve clinical outcomes.