10 research outputs found
Bar diagrams showing hepatic triglyceride content (A), plasma leptin (B), and insulin concentrations (C), and percentage of adipose visceral tissue (D), expressed as the mean±sd of 8 animals, for control and SLE mice at the weeks of sacrifice.
<p><b>E.</b> Bar diagrams showing the relative amount of P-Tyr-STAT-3 protein in liver tissue, expressed as the mean ± sd of values from 8 animals, from control (CT) and BWF1 (SLE) mice. The amount of protein loaded was confirmed by the Bradford method, and the uniformity of protein loading in each lane was assessed by determining the signal of β–actin as a control-loading protein.* <i>P</i><0.05, ** <i>P</i><0.01.</p
Genes whose expression was altered in visceral adipose tissue from 16-week old SLE <i>vs</i> CT mice.
<p>Genes whose expression was altered in visceral adipose tissue from 16-week old SLE <i>vs</i> CT mice.</p
BFWF1 mice, aged 36 weeks, showed increased kidney pathology.
<p>Hystological analysis of individual inflammatory (<b>A</b>) and glomerular hypercellularity scores (<b>B</b>) for CT and SLE mice, evaluated as described in the Material and Methods section. Representative photographs of renal sections from control (CT) (<b>C</b>) and BWF1 (SLE) (<b>D,E</b>) mice at the age of 36 weeks (H&E staining, light microscopy, original magnification ×40). Arrows indicate mesangial glomerular proliferation (<b>D</b>) and cellular extracapillary half-moon (<b>E</b>).</p
Bar diagrams showing the levels of AKT (A), IRS-1 (B) and RPS6K (C) protein in adipose tissue, and PPARγ (D), mTOR (E), and RPS6K (F) protein in liver tissue, expressed as the mean ± sd of values from 8 animals aged 16 weeks, for control (CT) and BWF1 (SLE) mice.
<p>The amount of protein loaded was confirmed by the Bradford method, and the uniformity of protein loading in each lane was assessed by determining the signal of β–actin as a control-loading protein. A representative autoradiography from a Western blot determination of two animals per group is shown. # <i>P</i> = 0.05, * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001.</p
A. Bar diagram showing solid food consumption, expressed as the mean±sd of g of pelleted diet consumed per day and animal, at different times (weeks) for control and SLE mice (8 animals per group).
<p><b>B.</b> Body weight, expressed as the mean±sd in g at the beginning of the study (week 6) and for control and SLE mice (8 animals per group) at the weeks of sacrifice. * <i>P</i><0.05.</p
Genes whose expression was altered in livers from 16-week old SLE <i>vs</i> CT mice.
<p>Genes whose expression was altered in livers from 16-week old SLE <i>vs</i> CT mice.</p
Bar diagrams showing IL-2 (A), IL-17 (B), MCP-1 (C), IL-4 (D), IL-5 (E), IL-10 (F), IL-13 (G), M-CSF (H), TNFα (I), and VEGF (J) concentrations in the supernatant of stimulated cultured splenocytes (see Material and Methods), expressed as the mean±sd of 8 cultures from separate animals, for control and SLE mice at week 36. * <i>P</i><0.05, ** <i>P</i><0.01.
<p>Bar diagrams showing IL-2 (A), IL-17 (B), MCP-1 (C), IL-4 (D), IL-5 (E), IL-10 (F), IL-13 (G), M-CSF (H), TNFα (I), and VEGF (J) concentrations in the supernatant of stimulated cultured splenocytes (see Material and Methods), expressed as the mean±sd of 8 cultures from separate animals, for control and SLE mice at week 36. * <i>P</i><0.05, ** <i>P</i><0.01.</p
Resilience to Pain-Related Depression in σ<sub>1</sub> Receptor Knockout Mice Is Associated with the Reversal of Pain-Induced Brain Changes in Affect-Related Genes
Mice lacking the σ1 receptor chaperone
(σ1R–/–) are resilient to
depressive-like
behaviors secondary to neuropathic pain. Examining the resilience’s
brain mechanisms could help develop conceptually novel therapeutic
strategies. We explored the diminished motivation for a natural reinforcer
(white chocolate) in the partial sciatic nerve ligation (PSNL) model
in wild-type (WT) and σ1R–/– mice. In the same mice, we performed a comprehensive reverse transcription
quantitative PCR (qPCR) analysis across ten brain regions of seven
genes implicated in pain regulation and associated affective disorders,
such as anxiety and depression. PSNL induced anhedonic-like behavior
in WT but not in σ1R–/– mice.
In WT mice, PSNL up-regulated dopamine transporter (DAT) and its rate-limiting
enzyme, tyrosine hydroxylase (Th), in the ventral tegmental area (VTA)
and periaqueductal gray (PAG) as well as the serotonin transporters
(SERT) and its rate-limiting enzyme tryptophan hydroxylase 2 (Tph2)
in VTA. In addition, μ-opioid receptor (MOR) and σ1R were up-regulated in PAG, and MOR was also elevated in the
somatosensory cortex (SS) but down-regulated in the striatum (STR).
Finally, increased BDNF was found in the medial prefrontal cortex
(mPFC) and hypothalamus (HPT). Sham surgery also produced PSNL-like
expression changes in VTA, HPT, and STR. Genetic deletion of the σ1R in mice submitted to PSNL or sham surgery prevented changes
in the expression of most of these genes. σ1R is
critically involved in the supraspinal gene expression changes produced
by PSNL and sham surgery. The changes in gene expression observed
in WT mice may be related to pain-related depression, and the absence
of these changes observed in σ1R–/– mice may be related to resilience
Synthesis and Biological Evaluation of the 1‑Arylpyrazole Class of σ<sub>1</sub> Receptor Antagonists: Identification of 4‑{2-[5-Methyl-1-(naphthalen-2-yl)‑1<i>H</i>‑pyrazol-3-yloxy]ethyl}morpholine (S1RA, E‑52862)
The synthesis and pharmacological activity of a new series
of 1-arylpyrazoles as potent σ<sub>1</sub> receptor (σ<sub>1</sub>R) antagonists are reported. The new compounds were evaluated
in vitro in human σ<sub>1</sub>R and guinea pig σ<sub>2</sub> receptor (σ<sub>2</sub>R) binding assays. The nature
of the pyrazole substituents was crucial for activity, and a basic
amine was shown to be necessary, in accordance with known receptor
pharmacophores. A wide variety of amines and spacer lengths between
the amino and pyrazole groups were tolerated, but only the ethylenoxy
spacer and small cyclic amines provided compounds with sufficient
selectivity for σ<sub>1</sub>R vs σ<sub>2</sub>R. The
most selective compounds were further profiled, and compound <b>28</b>, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1<i>H</i>-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high
activity in the mouse capsaicin model of neurogenic pain, emerged
as the most interesting candidate. In addition, compound <b>28</b> exerted dose-dependent antinociceptive effects in several neuropathic
pain models. This, together with its good physicochemical, safety,
and ADME properties, led compound <b>28</b> to be selected as
clinical candidate
Synthesis and Biological Evaluation of a New Series of Hexahydro‑2<i>H</i>‑pyrano[3,2‑<i>c</i>]quinolines as Novel Selective σ<sub>1</sub> Receptor Ligands
The
synthesis and pharmacological activity of a new series of hexahydro-2<i>H</i>-pyrano[3,2-<i>c</i>]quinoline derivatives as
potent σ<sub>1</sub> receptor (σ<sub>1</sub>R) ligands
are reported. This family, which does not contain the highly basic
amino group usually present in other σ<sub>1</sub>R ligands,
showed high selectivity over the σ<sub>2</sub> receptor (σ<sub>2</sub>R). The activity was shown to reside in only one of the four
possible diastereoisomers, which exhibited a perfect match with known
σ<sub>1</sub>R pharmacophores. A hit to lead program based on
a high-throughput screening hit (<b>8a</b>) led to the identification
of compound <b>32c</b>, with substantially improved activity
and physicochemical properties. Compound <b>32c</b> also exhibited
a good ADMET (absorption, distribution, metabolism, excretion, toxicity)
profile and was identified as a σ<sub>1</sub>R antagonist on
the basis of its analgesic activity in the mouse capsaicin and formalin
models of neurogenic pain