Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes.

Aims: Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations.

Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABA(C) receptors.

The enantiomers of 3F-GABA were evaluated on GABA(C) receptors. Both enantiomers were agonists, with the (R)-enantiomer being an order of magnitude more potent. This result is consistent with a folded binding mode for GABA, a conclusion which suggests a different binding mode to that found in the related but pharmacologically distinct GABA(A) receptors.

Successful treatment of nephrotic syndrome caused by recurrent IgA nephropathy with chronic active antibody-mediated rejection three years after kidney transplantation.

Here, we report the successful treatment of a 38-yr-old Japanese man diagnosed with recurrent immunoglobulin A nephropathy (IgAN) with chronic active antibody-mediated rejection (CAAMR), three yr after undergoing living-related donor kidney transplantation. Immediately after transplantation, the allograft function was well maintained with a serum creatinine (S-Cr) level of <1.8 mg/dL.

Lipogenic gene expression in abdominal adipose and liver tissues of diet-induced overweight cats.

The effect of overweight status on the expression of SREBP-1c and downstream lipogenic genes, such as ATP citrate lyase (ACL) and fatty acid synthase (FAS), in abdominal adipose and liver tissues was determined in cats using a diet-induced weight gain model. ACL and SREBP-1c mRNA expression was significantly reduced (∼65% and 20%, respectively) in liver tissue, whereas FAS and SREBP-1c expression was significantly increased (∼80% and 45%, respectively) in abdominal omental adipose tissue of overweight animals as compared to healthy animals. Additionally, ACL, FAS, and SREBP-1c expression was significantly reduced by ∼50%, 75%, and 70%, respectively, in abdominal subcutaneous adipose tissue of overweight animals.

Identification of regions responsible for heparin-induced amyloidogenesis of human serum amyloid A using its fragment peptides.

Human serum amyloid A (SAA) is a precursor protein of amyloid fibrils. Although several studies have been performed, a detailed understanding of the molecular mechanism for SAA fibrillation remains elusive. Glycosaminoglycans such as heparin are suggested to serve as scaffolds in amyloid fibril formation in some cases.

Effects of intestinal microflora on superoxide dismutase activity in the mouse cecum.

In the antioxidant defense system, superoxide dismutase (SOD) catalyzes the breakdown of superoxide into hydrogen peroxide and oxygen. In the cecum, the influence of intestinal microflora on SOD activity is unknown. In this study, we used germ-free (GF) mice to examine the effect of intestinal microflora on SOD activity in the cecum, and SOD activity was compared between GF and conventional (CV) mice.

Inclined foot switches for surgical microscopes: a comfortable design for seated surgeons: technical note.

During microneurosurgical procedures, surgeons sitting on a stool may experience muscular fatigue in the lower half of the body due to repeat manipulation of foot switches controlling the surgical microscope. The mechanisms contributing to this fatigue were examined and a method developed for fatigue reduction. The switch panel harboring the pedals was originally designed to be placed horizontally, but was inclined toward the surgeon with a sandbag placed under the panel.

Medicinal chemistry of ρ GABAC receptors.

The inhibitory neurotransmitter, GABA, is a low-molecular-weight molecule that can achieve many low-energy conformations, which are recognized by GABA receptors and transporters. In this article, we assess the structure-activity relationship profiles of GABA analogs at the ionotropic ρ GABA(C) receptor. Such studies have significantly contributed to the design and development of potent and selective agonists and antagonists for this subclass of GABA receptors.

Anchoring of methylmethacrylate filler to the calvarium--technical note.

Implanted methylmethacrylate may be unexpectedly displaced due to poor adherence to the bone. We developed a simple technique to fix the material plugging the burr holes for use primarily in cosmetically important areas. At the closure of craniotomy, 2-3 small drill holes are made at the rim of the craniotomy burr hole.

Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety.

Aims: In this study, we examined the inhibitory effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major cannabinoids, on the activity of human cytochrome P450 (CYP) 3A enzymes. Furthermore, we investigated the kinetics and structural requirement for the inhibitory effect of CBD on the CYP3A activity.

Main Methods: Diltiazem N-demethylase activity of recombinant CYP3A4, CYP3A5, CYP3A7, and human liver microsomes (HLMs) in the presence of cannabinoids was determined.

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology.

Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (19, K B = 10 μM) and selectivity (greater than 100 times at ρ1 GABAC receptors as compared to α1β2γ2L GABAA and GABAB(1b,2) receptors) was obtained.

Molecular characterization of structure and tissue distribution of chicken neurotensin receptor.

Neurotensin, a tridecapeptide, is distributed in a wide range of tissues and exhibits multiple functions through its receptors. Hitherto molecular characterization of the neurotensin receptor has been reported in mammalian, amphibian, and fish species but not in avian species. In this study, we cloned the cDNA encoding chicken neurotensin receptor from the duodenum and characterized its primary structure, biological activity and distribution in the gastrointestinal tract.

Medullary ray injury in renal allografts.

Non-immune injury leading to interstitial fibrosis and tubular atrophy (IF/TA) in renal allografts has various etiologies, but pathological means of verification have yet to be developed. Medullary ray injury (MRI) is a pathological feature of many non-immune injuries inducing IF/TA and pathological determination of calcineurin inhibitor (CNI) toxicity proceeding to striped fibrosis. We investigated the contribution of CNI toxicity to MRI and other non-immune etiologies related to IF/TA.

Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors.

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein, a major causal factor for atherosclerosis. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), a major component of marijuana, has suggested to suppress atherosclerosis. Although Δ(9)-THC seems to be attractive for the prevention of atherosclerosis, there is no information about whether or not 15-LOX isoform can be inhibited by Δ(9)-THC.

The relationship between clinicopathological factors and the reduction of pyrimidine nucleoside phosphorylase activity after preoperative administration of 5'-deoxy-5-fluorouridine.

Aim: The response to fluoropyrimidine chemotherapeutic drugs is different in individual tumors. Predictive biomarkers of antitumor effects by these drugs are unknown. 5'-Deoxy-5-fluorouridine (5'-DFUR), a fluoro-pyrimidine chemotherapeutic drug, is converted to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase).

Possible difficult laryngoscopy caused by masticatory muscle tendon-aponeurosis hyperplasia: we anesthesiologists should be aware of this disease.

Masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) is a new disease entity characterized by limited mouth opening due to contracture of the masticatory muscles resulting from hyperplasia of tendons and aponeuroses. The other clinical feature is that the face of the patient with this disease displays a square mandible configuration. Muscle relaxants provide no relief for the limited mouth-opening ability.

Activation of the transcription factor c-Jun in acute cellular and antibody-mediated rejection after kidney transplantation.

c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined.

Depth-adjustable fixation of external ventricular drains to counteract obstruction in tight ventricles.

Tightness of the lateral ventricle may result in mechanical obstruction of an external ventricular drain (EVD). We propose a modified EVD fixation method that allows retraction of the EVD to reopen the drainage. We used this technique in patients requiring long-term EVD placement in the frontal horn who were expected to develop tightening of the ventricle.

Intramolecular acyl migration and enzymatic hydrolysis of a novel monoacylated ascorbic acid derivative, 6-O-dodecanoyl-2-O-alpha-d-glucopyranosyl-L-ascorbic acid.

A stable ascorbic acid derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), exhibits vitamin C activity in vitro and in vivo after enzymatic hydrolysis to ascorbic acid. AA-2G has been approved by the Japanese Government as a quasi-drug principal ingredient in skin care and as a food additive. In order to achieve efficient action as an ascorbic acid source, a pro-vitamin C agent, on a variety of cells or tissues, we have synthesized a series of monoacyl AA-2G derivatives.

Defective human T-lymphotropic virus type 1 provirus in asymptomatic carriers.

Few studies have specifically examined defective provirus in asymptomatic human T-lymphotropic virus Type 1 (HTLV-1) carriers and its relation to proviral DNA loads (PVLs). To assess the significance of defective provirus in asymptomatic carriers, we examined PVLs in peripheral blood mononuclear cells of 208 asymptomatic HTLV-1 carriers. The mean PVLs determined using primers for the pol region were less than that for the pX region in these carriers.

Characteristics of elderly Japanese patients with severe burns.

In this study, we report the clinical characteristics of elderly Japanese patients with severe burns. We studied the clinical features of 76 adult patients with severe burns, 35 of whom (46.1%) were ≥65 years old.

Extraspinal ependymoma of the broad ligament.

Extraspinal ependymoma is a rare tumor, occurring most commonly in the sacrococcygeal region, and only a small number of cases have been reported to arise in the uterine ligament. Herein is reported a case of extraspinal ependymoma arising in the broad ligament of a 27-year-old woman. The lesion was 14 cm in diameter with an intra-abdominal implant in the omentum.

Multiple integrations of human T-lymphotropic virus type 1 proviruses in the engrafted cells from the asymptomatic carriers in NOD/SCID/gammacnull mice.

Objectives: Successful engraftment of human T-lymphotropic virus type 1 (HTLV-1)-infected cells and a marked increase of proviral DNA loads (PVLs) in non-obese diabetic/severe combined immunodeficient (NOD/SCID)/gammac(null) (NOG) mice have been reported. Whether the increased PVL in transplanted mice is due to the new infection of HTLV-1 was examined.

Methods: Mononuclear cells from 3 NOG mice with primary engraftment from asymptomatic HTLV-1 carriers were transplanted into a second group of NOG mice.

Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes.

Inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, on catalytic activities of human cytochrome P450 (CYP) 1 enzymes were investigated. These cannabinoids inhibited 7-ethoxyresorufin O-deethylase activity of recombinant CYP1A1, CYP1A2, and CYP1B1 in a competitive manner. CBD most potently inhibited the CYP1A1 activity; the apparent K(i) value (0.