Convergent Total Synthesis of (-)-Cyclopamine.

A concise and enantioselective total synthesis of the alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a synthesis of the -6,5-heterobicycle via a strain-inducing halocyclization process, a key Tsuji-Trost cyclization to construct the fully substituted, spirocyclic THF motif with exquisite diastereocontrol, and a late-stage ring-closing metathesis (RCM) reaction to forge the central tetrasubstituted olefin.

Perfluorooctane sulfonate induces heart toxicity involving cardiac apoptosis and inflammation in rats.

Perfluorooctane sulfonate (PFOS) is a persistent pollutant that exerts toxicity and induces cardiogenesis in humans and animals. Yet, the effect of PFOS exposure on cardiac toxicity in adult rats has, to our knowledge, not been reported and the mechanism still remains unknown. The present study aimed to investigate the toxicity of PFOS on rat hearts and any associated mechanisms.

Enantiodivergent Formation of C-P Bonds: Synthesis of P-Chiral Phosphines and Methylphosphonate Oligonucleotides.

Phosphorus Incorporation (PI, abbreviated Π) reagents for the modular, scalable, and stereospecific synthesis of chiral phosphines and methylphosphonate nucleotides are reported. Synthesized from limonene oxide, this reagent class displays an unexpected reactivity profile and enables access to chemical space distinct from that of the Phosphorus-Sulfur Incorporation reagents previously disclosed. Here, the adaptable phosphorus(V) scaffold enables sequential addition of carbon nucleophiles to produce a variety of enantiopure C-P building blocks.

Lysophosphatidic acid precursor levels decrease and an arachidonic acid-containing phosphatidylcholine level increases in the dorsal root ganglion of mice after peripheral nerve injury.

In the current study, we aimed to analyze the lipid changes in the dorsal root ganglion (DRG) after sciatic nerve transection (SNT) using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). We found that the arachidonic acid-containing phosphatidylcholine (AA-PC), PC(16:0/20:4) largely increased, while PC(16:0/18:1), PC(18:0/18:1) and phosphatidic acid (PA)(36:2) levels largely decreased in the DRG following nerve injury. Previous studies show that the increase in PC(16:0/20:4) was associated with neuropathic pain and that decrease in PC(16:0/18:1), PC(18:0/18:1), and PA(36:2) were due to producing lysophosphatidic acid (LPA), an initiator for neuropathic pain.

Synthesis of Z- or E-Trisubstituted Allylic Alcohols and Ethers by Kinetically Controlled Cross-Metathesis with a Ru Catechothiolate Complex.

The first examples of kinetically controlled cross-metathesis reactions that generate Z- or E-trisubstituted alkenes are disclosed. Transformations are catalyzed by ≤6.0 mol % of a Ru catechothiolate complex and afford trisubstituted allylic alcohols and ethers in up to 81% yield and >98% stereoisomeric purity.

Comparison of hip muscle volume between fit-and-fill stem and tapered-wedge stem after total hip arthroplasty using the anterolateral approach.

Background: In total hip arthroplasty (THA) surgery, hip muscle preservation is important in strengthening the stability of the hip and improving the activities of the patient. However, whether the type of femoral stem affects the recovery of the hip muscles remains unknown. The aim of this study was to compare the postoperative hip muscle recovery among femoral stem varieties after THA.

Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury.

Peripheral nerve injury induces substantial molecular changes in the somatosensory system that leads to maladaptive plasticity and cause neuropathic pain. Understanding the molecular pathways responsible for the development of neuropathic pain is essential to the development of novel rationally designed therapeutics. Although lipids make up to half of the dry weight of the spinal cord, their relation with the development of neuropathic pain is poorly understood.

Kinetically E-selective macrocyclic ring-closing metathesis.

Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation).

Increased arachidonic acid-containing phosphatidylcholine is associated with reactive microglia and astrocytes in the spinal cord after peripheral nerve injury.

Peripheral nerve injury (PNI) triggers cellular and molecular changes in the spinal cord. However, little is known about how the polyunsaturated fatty acid-containing phosphatidylcholines (PUFA-PCs) are regulated in the spinal cord after PNI and the association of PUFA-PCs with the non-neuronal cells within in the central nervous system (CNS). In this study, we found that arachidonic acid-containing phosphatidylcholine (AA-PC), [PC(16:0/20:4)+K](+), was significantly increased in the ipsilateral ventral and dorsal horns of the spinal cord after sciatic nerve transection, and the increased expression of [PC(16:0/20:4)+K](+) spatiotemporally resembled the increase of reactive microglia and the astrocytes.

[Zileuton, a 5-lipoxygenase inhibitor, attenuates mouse microglial cell-mediated rotenone toxicity in PC12 cells].

Objective: To examine the effect of a selective inhibitor of 5-lipoxygenase (5-LOX) zileuton on microglia-mediated rotenone neurotoxicity.

Methods: The supernatant from different concentrations of rotenone-stimulated mouse microglia BV2 cells was used as the conditioned media (CM) for PC12 cells. The viability of PC12 cells was determined by MTT assay and lactate dehydrogenase (LDH) release.

[Effect of histone deacetylase inhibitor NL101 on rat neurons].

Objective: To investigate the protective effect of histone deacetylase inhibitor NL101 on L-homocysteine (HCA)-induced toxicity in rat neurons, and the toxic effect on normal rat neurons.

Methods: In the presence of NL101 at various concentrations, HCA (5 mmol/L)-induced changes in cell density, necrosis, and viability were determined in the mixed cultures of rat cortical cells and the primary cultures of rat neurons. The direct effect of NL101 on primary neurons was also observed in the absence of HCA.

[Antioxidative effects of cysteinyl leukotriene receptor antagonists montelukast and HAMI 3379 on ischemic injury in rat cortical neurons in vitro].

Objective: To investigate the antioxidative effects of two cysteinyl leukotriene receptors antagonists (CysLT1R and CysLT2R) montelukast and HAMI 3379 on ischemic injury of rat cortical neurons in vitro.

Methods: Cultured rat cortical neurons were pretreated with CysLT1R antagonist montelukast and CysLT2R antagonist HAMI 3379, and then exposed to oxygen-glucose deprivation/recovery (OGD/R）or H2O2. Reactive oxygen species (ROS) mitochondrial membrane potential (MMP) depolarization, neuronal viability and lactate dehydrogenase (LDH) release were determined.

Regulation of rotenone-induced microglial activation by 5-lipoxygenase and cysteinyl leukotriene receptor 1.

The 5-lipoxygenase (5-LOX) products cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators. CysLTs mediate their biological actions through activating CysLT receptors (CysLT(1)R and CysLT(2)R). We have recently reported that 5-LOX and CysLT(1)R mediated PC12 cell injury induced by high concentrations of rotenone (0.

Cysteinyl leukotriene receptor 1 mediates LTD4-induced activation of mouse microglial cells in vitro.

Aim: To investigate the roles of cysteinyl leukotriene receptors CysLT1R and CysLT2R in leukotriene D4 (LTD4)-induced activation of microglial cells in vitro.

Methods: Mouse microglial cell line BV2 was transfected with pcDNA3.1(+)-hCysLT1R or pcDNA3.

HAMI 3379, a CysLT2 receptor antagonist, attenuates ischemia-like neuronal injury by inhibiting microglial activation.

The cysteinyl leukotrienes (CysLTs) are inflammatory mediators closely associated with neuronal injury after brain ischemia through the activation of their receptors, CysLT1R and CysLT2R. Here we investigated the involvement of both receptors in oxygen-glucose deprivation/recovery (OGD/R)-induced ischemic neuronal injury and the effect of the novel CysLT2R antagonist HAMI 3379 [3-({[(1S,3S)-3- carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo-hexyloxy)butoxy]phenyl}propoxy)benzoic acid] in comparison with the CysLT1R antagonist montelukast. In primary neurons, neither the nonselective agonist leukotriene D4 (LTD4) nor the CysLT2R agonist N-methyl-leukotriene C4 (NMLTC4) induced neuronal injury, and HAMI 3379 did not affect OGD/R-induced neuronal injury.

Intracerebroventricular injection of HAMI 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats.

Cysteinyl leukotrienes (CysLTs) induce inflammatory responses by activating their receptors, CysLT(1)R and CysLT(2)R. We recently reported that CysLT(2)R is involved in neuronal injury, astrocytosis and microgliosis after focal cerebral ischemia in rats. Here, we determined whether HAMI 3379, a selective CysLT(2)R antagonist, protects against acute brain injury after focal cerebral ischemia in rats.