Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of senile dementia. Recently, scientists have put significant effort into exploring the molecular mechanisms involved in the pathological processes leading to the disease. A vast number of studies have focused on understanding the nitric oxide (NO) signaling pathway, which culminates with the phosphorylation of the transcription factor cAMP-responsive element-binding protein (CREB) through the increase of the second messenger cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase. This book chapter provides an overview of the progress being made in modulating the hippocampal synaptic transmissions, which are critical for learning and memory, by targeting the different components of the NO/cGMP/CREB phosphorylation signaling pathway. Furthermore, a description of recent research on this pathway through the use of phosphodiesterase inhibitors is emphasized

Black hole shadow, photon ring and lensing ring in the cold dark matter halo

The Schwarzschild black hole in the cold dark matter (CDM) halo is deeply studied, and the radiation laws of the thin accretion disk near the black hole is discussed and summarized. The light orbits around the black hole are calculated. According to the number of times that the light from the north pole passes through the equatorial plane of the black hole, the light orbits can be divided into three categories. At the same time, the innermost stable circular orbit of the black hole is also calculated. By analyzing the calculation results of radiation intensity of three kinds of radiation which emitted by thin accretion disk on the equatorial plane of black hole and observed at infinity away from the north pole of black hole, the radiation laws of the thin accretion disk of Schwarzschild black hole suitable for the background of the CDM halo is obtained.Comment: 21pages. arXiv admin note: text overlap with arXiv:2105.15073 by other author

Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development. © 2012 Elsevier Ltd. All rights reserved

Position and Role of the BK Channel α Subunit S0 Helix Inferred from Disulfide Crosslinking

The position and role of the unique N-terminal transmembrane (TM) helix, S0, in large-conductance, voltage- and calcium-activated potassium (BK) channels are undetermined. From the extents of intra-subunit, endogenous disulfide bond formation between cysteines substituted for the residues just outside the membrane domain, we infer that the extracellular flank of S0 is surrounded on three sides by the extracellular flanks of TM helices S1 and S2 and the four-residue extracellular loop between S3 and S4. Eight different double cysteine–substituted alphas, each with one cysteine in the S0 flank and one in the S3–S4 loop, were at least 90% disulfide cross-linked. Two of these alphas formed channels in which 90% cross-linking had no effect on the V50 or on the activation and deactivation rate constants. This implies that the extracellular ends of S0, S3, and S4 are close in the resting state and move in concert during voltage sensor activation. The association of S0 with the gating charge bearing S3 and S4 could contribute to the considerably larger electrostatic energy required to activate the BK channel compared with typical voltage-gated potassium channels with six TM helices

Anti-Cocaine Compositions and Treatment

Embodiments of the invention disclosed herein generally relate to anti-cocaine therapeutics. Specifically, some embodiments of the invention relate to highly efficient, thermostable, and long-lasting cocaine esterase (CocE) mutants that can protect against the toxic and reinforcing effects of cocaine in subjects. Provided herein are mutant CocE polypeptides displaying thermostable esterase activity. Also provided are methods of treating cocaine-induced conditions in a subject in need via administration of mutant CocE as well as methods for high-throughput screening of candidate esterase polypeptides

Deep transcranial magnetic stimulation for schizophrenia: a systematic review

BackgroundThe efficacy and safety of deep transcranial magnetic stimulation (dTMS) as an intervention for schizophrenia remain unclear. This systematic review examined the efficacy and safety of dTMS for schizophrenia.MethodsA systematic search of Chinese (WanFang and Chinese Journal Net) and English databases (PubMed, EMBASE, PsycINFO, and Cochrane Library) were conducted.ResultsThree randomized clinical trials (RCTs) comprising 80 patients were included in the analyses. Active dTMS was comparable to the sham treatment in improving total psychopathology, positive symptoms, negative symptoms, and auditory hallucinations measured by the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the Auditory Hallucinations Rating Scale (AHRS), respectively. Only one RCT reported the effects on neurocognitive function measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB), suggesting that dTMS may only improve one Stockings of Cambridge measure (i.e., subsequent times for five move problems). All three studies reported overall discontinuation rates, which ranged from 16.7% to 44.4%. Adverse events were reported in only one RCT, the most common being tingling/twitching (30.0%, 3/10), head/facial discomfort (30.0%, 3/10), and back pain (20.0%, 2/10).ConclusionThis systematic review suggests that dTMS does not reduce psychotic symptoms in schizophrenia, but it shows potential for improving executive functions. Future RCTs with larger sample sizes focusing on the effects of dTMS on psychotic symptoms and neurocognitive function in schizophrenia are warranted to further explore these findings