Elevated adrenocorticotropic hormone and cortisol levels in a patient with medullary carcinoma of the thyroid containing ectopic immunoreactive corticotropin-releasing hormone and bombesin

Pituitary adrenocorticotropic hormone-dependent Cushing’s syndrome due to ectopic production of corticotropin-refeasing hormone (CRH) or bombesin (gastrin-releasing peptide) is an extremely rare cause of pituitary adrenocorticotropic hormone (ACTH) hypersecretion. We report a patient with elevated ACTH and cortisol levels due to ectopic secretion of both bombesin and CRH by metastatic medullary carcinoma of the thyroid (MCT). A 45-year-old man was investigated because of diabetes insipidus and visual field disturbances due to suprasellar metastasis of the MCT. On physical examination, he was a chronically ill man with a body mass index of 18.5 and was darkly pigmented but without other features typical of Cushing’s syndrome. Hypogonadotropic hypogonadism, thyroid-stimulating hormone (TSH) deficiency, and hyperprolactinemia were due to pituitary stalk disorder, in light of these deficiencies, we were surprised to find elevated plasma ACTH, cortisol, and growth hormone (GH) levels throughout the day. Plasma ACTH at 9am was 118 pg/ml and plasma cortisol was 859 nmol/L. At 12pm, ACTH was 89 pg/ml whereas plasma cortisol was 540 nmol/L. Urinary 17 OH CS were elevated (38 nmol/24 hr). The mean of the four-point day curve for GH was elevated. Plasma electrolytes were normal. The presence of both CRH and bombesin was documented by immunocytologic studies in the metastases (lymph node and suprasellar biopsy). ACTH was not found in any of the metastases. Because of the close proximity of the suprasellar metastasis to the portal pituitary circulation, CRH and bombesin could have been readily provided to the pituitary corticotrophs.     

Colitis generates remote antinociception in rats: the role of the l-arginine/NO/cGMP/PKG/KATP pathway and involvement of cannabinoid and opioid systems

Objective and design

The aim of this study was to investigate the possible involvement of the NO/cGMP/PKG/K _ATP ⁺ pathway, cannabinoids and opioids in remote antinociception associated with 2,4,6-trinitrobenzene sulph onic acid (TNBS)-induced colitis.

Methods

TNBS-induced colitis was induced by intracolonic administration of 20 mg of TNBS in 50 % ethanol. After induction, carrageenan (500 μg/paw) or prostaglandin (PG) E₂ (100 ng/paw) was injected in the rat’s plantar surface and hypersensitivity was evaluated by the electronic von Frey test. Rats were pre-treated with l-Noarg one hour before carrageenan injection. l-Arginine was given 10 min before l-Noarg injections. ODQ, KT 5823, glibenclamide (Glib), naloxone and AM 251 or AM 630 were administered 30 min prior to carrageenan or PGE₂ treatments.

Results

Colitis induction by TNBS reduced PGE₂ or carrageenan-induced hypersensitivity. Antinociception produced by TNBS-induced colitis was reversed significantly (P < 0.05) by l-Noarg, ODQ, KT 5823, glibenclamide, naloxone, AM251 and AM630 treatments.

Conclusions

TNBS-induced colitis causes antinociception in the rat paw. This disorder appears to be mediated by activation of the NO/cGMP/PKG/K_ATP pathway, endocannabinoids and endogenous opioids. This information may contribute to a better understanding of peripheral neurological dysfunctions occurring in Crohn’s disease.     

Anti-inflammatory effect of quinoline alkaloid skimmianine isolated from Ruta graveolens L.

Objective

The present study evaluates the anti-inflammatory effect of the quinoline alkaloid skimmianine (SKM), isolated from Ruta graveolens L., against carrageenan-induced acute inflammation.

Methods

SKM at a dose of 5.0 mg/kg body weight was found to be the minimal concentration for maximal edema inhibition. Carrageenan suspension was administered into the sub-plantar tissue of the right hind paw 1 h after SKM and diclofenac (20 mg/kg) administration (i.p.). Paw edema was determined 3 h after carrageenan administration. The rats were then killed and mRNA expressions of TNF-α and IL-6, levels of PGE₂ and TBARS, activities of COX-2, 5-LOX, SOD, catalase, glutathione peroxidase (GPx) and myeloperoxidase (MPO) and the level of nitrite were measured.

Results

SKM treatment resulted in a decrease in the mRNA levels of TNF-α and IL-6, which are upstream events of the inflammatory cascade. The levels of PGE₂ and NO and the activities of COX-2 and 5-LOX were also significantly reduced after SKM treatment. Neutrophil infiltration, lipid peroxidation and associated oxidative stress in the paw tissue were reduced following SKM treatment.

Conclusion

These results support the anti-inflammatory properties of skimmianine and its multi-targeted mechanism of action, suggesting its potential therapeutic efficacy in various inflammatory diseases.     

Activation of hippocampal MEK1 contributes to the cumulative antinociceptive effect of electroacupuncture in neuropathic pain rats

Background

Electroacupuncture (EA) intervention can relieve a variety of pain; however, optimal EA protocols have not been clearly determined. In addition, although central mitogen-activated protein kinase kinase (MEK) signaling has been shown to be involved in the antinociceptive effect of acupuncture stimulation, its characteristics at different time-points of EA intervention have not been fully elucidated. Therefore, the present study investigated the relationship between the effects of different numbers of EA intervention sessions and the activation of MEK1 in the hippocampus and hypothalamus in a rat model of neuropathic pain.

Methods

After ligation of the left sciatic nerve, which induces chronic constriction injury (CCI), the acupoints Zusanli (ST36) and Yanglingquan (GB34) were applied. The thermal withdrawal latency of the hind paw was used to evaluate the effect of EA on pain thresholds. Intra-hippocampus microinjection of PD98059, a MEK inhibitor, was performed to validate the involvement of MEK in EA analgesia. The hippocampus and hypothalamus were harvested to examine the phosphorylation levels of MEK (pMEK) by western blotting.

Results

In CCI rats, the thermal pain threshold of the affected hind paw decreased significantly relative to the control. Following subsequent daily EA interventions, CCI-induced ipsilateral hyperalgesia was markedly improved from day 4 and the analgesic effect of EA lasted 3 days after cessation of EA. Four sessions of EA markedly suppressed CCI-induced decrease of hippocampal pMEK1 (normalized to the total MEK level). In contrast, successive sessions of EA intervention gradually down-regulated the CCI-induced up-regulation of hypothalamic pMEK1 along with the increase numbers of EA intervention. However, EA did not exert the same analgesic effect after microinjection of PD98059 into the contralateral hippocampus during the first 3 days of EA intervention.

Conclusions

EA intervention can induce time-dependent cumulative analgesia in neuropathic pain rats after 4 successive sessions of daily EA intervention, which is at least in part related to the activation of hippocampal MEK1.

     

NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

Background

Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.

Methods

We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for in vitro experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.

Results

NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. In vitro, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1??- and TNF-??-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-??-induced MMP-9 expression through ??₁ integrin engagement. In vivo, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.

Conclusions

This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.     

Anti-arthritic activity of the Indian leafy vegetable Cardiospermum halicacabum in Wistar rats and UPLC–QTOF–MS/MS identification of the putative active phenolic components

Objectives

The present work was carried out to investigate the free radical scavenging activity of the ethanol extract of C. halicacabum leaves (EECH), to study its antioxidant properties and anti-rheumatic effects in Wistar rats with CFA-induced arthritis, and to profile the phenolic components thereof by LC–MS/MS.

Methods

The free radical scavenging activities of the extract was evaluated by NO and superoxide anion scavenging assays. Arthritis was induced to the albino Wistar rats by CFA. Fifteen days after CFA induction, arthritic rats received EECH orally at the doses of 250 and 500 mg/kg daily for 20 days. Diclofenac sodium was used as reference standard. EECH is subjected to LC–MS/MS analysis for the identification of phenolic compounds.

Results

The IC₅₀ value of the EECH to scavenge the NO and superoxide radicals are 83 and 60 μg/ml respectively. Ultrasonography and histology images of hind limb in EECH treated groups confirmed the complete cartilage regeneration. The LC/MS/MS analysis indicated the presence of anti-inflammatory compounds luteolin-7-O-glucuronide, apigenin-7-O-glucuronide and chrysoeriol.

Conclusion

These findings lend pharmacological support to the reported folkloric use of C. halicacabum in the treatment and management of painful, arthritic inflammatory conditions.     

Assessment of Dietary Restraint: Psychometric Properties of the Revised Restraint Scale in Hong Kong Adolescents

Background

The psychometric properties of the Revised Restraint Scale (RRS) have been well established in western populations but not in Chinese adolescents.

Purpose

This study investigated the psychometric properties of RRS and its validity in different subgroups for Hong Kong Chinese adolescents.

Method

In 2007, 909 Hong Kong students aged 12 to 18?years (55.3% boys) completed a questionnaire including demographic items, RRS, Eating Attitudes Test (EAT-26), and Motivation for Eating Scale (MFES)-physical. Moreover, subjects?? height and weight were measured. To examine the factor structure of RRS, the whole sample was randomly split into two groups (sample 1: N=454 and sample 2: N=455) for exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), respectively. Convergent and discriminant validity of RRS were investigated by correlating the RRS with EAT-26 and MFES-physical. Multigroup CFA was conducted to test the three-factor model of RRS in different sex, age, and weight status subgroups.

Results

Results of EFA for sample 1 revealed three strongly correlated factors for the RRS construct, and were supported by the CFA results in sample 2. Multigroup CFA further suggested that the three-factor model of RRS was stable across sex, age, and weight status subgroups.

Conclusions

A new three-factor model is proposed for Hong Kong adolescents in this study. In general, RRS is a reliable and valid measure of restrained eating for adolescents, regardless of sex, age, and weight status.     

Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats

Objective

We examined the effects of ZSTK474, a phosphatidylinositol 3-kinase (PI3K) inhibitor, on adjuvant-induced arthritis (AIA).

Methods

AIA was induced in Lewis rats by subcutaneous administration of Freund’s complete adjuvant at the base of the tail on day 0. ZSTK474 was orally administered once daily from day 10. The severity of AIA was assessed by measuring the hind paw volume. The number of lymphocytes in inguinal lymph nodes (ILN) was determined by flow cytometry. The in vitro effects of ZSTK474 on the cell proliferation, and the cytokines and prostaglandin E₂ (PGE₂) production were evaluated by BrdU method, ELISA and cytometric beads array.

Results

ZSTK474 ameliorated the progression of AIA. The temporary increases in the number of T cells in ILN, which occurred along with the appearance of arthritis, were inhibited in the ZSTK474-treated groups. In vitro studies revealed that ZSTK474 inhibited the production of IFNγ and IL-17 in concanavalin A-activated T cells. In vitro studies further revealed that ZSTK474 inhibited the proliferation and PGE₂ production by fibroblast-like synovial cells (FLS).

Conclusion

ZSTK474 demonstrated prophylactic efficacy in a rat model of rheumatoid arthritis (RA) through inhibition of T cell and FLS functions. It was suggested that the inhibitors of PI3K have therapeutic potential for RA.     

The involvement of the HO-1 pathway in the anti-inflammatory action of a sulfated polysaccharide isolated from the red seaweed Gracilaria birdiae

Objectives

The aim of this study was to investigate the involvement of the hemoxigenase-1 (HO-1) pathway in the anti-inflammatory action of a sulfated polysaccharide from the red seaweed Gracilaria birdiae (SP-Gb).

Methods

SP-Gb (5, 10 and 20?mg/kg) was administered to Wistar rats in a peritonitis model using carrageenan or a paw edema model using carrageenan or dextran. To analyze the involvement of HO-1 in the anti-inflammatory activity of SP-Gb, the animals were pretreated subcutaneously with a specific HO-1 inhibitor (ZnPP IX). To evaluate the systemic effects, SP-Gb (10?mg/kg) was administered to mice intraperitoneally before waiting for 48?h or for 14?days.

Results

SP-Gb (10?mg/kg) caused an anti-inflammatory effect that was evidenced by a decrease in leukocytes in the peritoneal cavity. SP-Gb also reduced the paw edema induced by carrageenan and inhibited the paw edema induced by dextran in the first half-hour. After being inhibited by ZnPP IX, the anti-inflammatory effect of SP-Gb on carrageenan-induced rat paw edema was not observed. SP-Gb did not cause mortality or significant changes in the biochemical, hematological and histopathological parameters.

Conclusion

SP-Gb may be used as a tool for further investigations into the inflammatory processes associated with the hemoxigenase-1 pathway.     

Accumulation of marginal zone B cells and accelerated loss of follicular dendritic cells in NF-κB p50-deficient mice

Background

We previously showed that local use of periodate oxidized ATP (oATP, a selective inhibitor of P2X7 receptors for ATP) in rat paw treated with Freund's adjuvant induced a significant reduction of hyperalgesia Herein we investigate the role of oATP, in the rat paws inflamed by carrageenan, which mimics acute inflammation in humans.

Results

Local, oral or intravenous administration of a single dose of oATP significantly reduced thermal hyperalgesia in hind paws of rats for 24 hours, and such effect was greater than that induced by diclofenac or indomethacin. Following oATP treatment, the expression of the pro-inflammatory chemokines interferon-gamma-inducible protein-10 (IP-10), mon ocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) within the inflamed tissues markedly decreased on vessels and infiltrated cells. In parallel, the immunohistochemical findings showed an impairment, with respect to the untreated rats, in P2X7 expression, mainly on nerves and vessels close to the site of inflammation. Finally, oATP treatment significantly reduced the presence of infiltrating inflammatory macrophages in the paw tissue.

Conclusion

Taken together these results clearly show that oATP reduces carrageenan-induced inflammation in rats.     

Endothelin-3 at low concentrations attenuates inflammatory responses via the endothelin B2 receptor

Objective

The aim of this study was to clarify a role of endothelins (ETs: ET-1, -2, and -3) and their receptors (ETA, ETB1, and ETB2) in inflammatory responses.

Methods

Male Wistar rats (180–220 g) were used. The effects of ETs in the absence or presence of the ETA antagonist BQ-123/the selective ETB2 antagonist BQ-788, and the effect of the selective ETB1 agonist IRL-1620 and the nonselective ETB agonist BQ-3020, on rat hind paw oedema induced by several proinflammatory substances were examined. The involvement of nitric oxide (NO) in the effects of ETs on the paw oedema was investigated using the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME).

Results

ET-3, which acts mainly on ETB, at low concentrations specifically inhibited platelet-activating factor (PAF)-induced paw oedema, whereas neither ET-1 nor ET-2, both of which act on ETA and ETB, showed inhibitory activity. The inhibition by ET-1 and ET-3 (each 0.5 pmol/paw) in the presence of BQ-123 (66.4 ± 6.7 % and 65.4 ± 22.6 %, respectively), was comparable to that by ET-3 (0.5 pmol/paw) alone (65.4 ± 10.9 %), whereas neither ET-1 nor ET-3 in the presence of BQ-788 showed inhibitory activity. BQ-3020 (0.5 pmol/paw) inhibited the oedema by 50.9 ± 6.0 %, whereas IRL-1620 showed almost no activity. Additionally, L-NAME markedly attenuated the inhibitory effects of ET-3 on PAF-induced paw oedema. These results indicate that ETB2 may mediate NO production and attenuation of PAF-induced inflammatory responses. Moreover, ET-3 (0.5 pmol/paw) inhibited the oedema induced by ET-1 at higher dose and zymosan by 76.6 ± 11.0 and 85.4 ± 13.6 %, respectively, indicating that ET-3 at lower concentrations inhibits the paw oedema induced by various inflammatory substances.

Conclusions

ET-3 at low concentrations may attenuate inflammatory responses via ETB2 activation and NO production.     

CCR4 Agonists CCL22 and CCL17 are Elevated in Pediatric OMS Sera: Rapid and Selective Down-Regulation of CCL22 by ACTH or Corticosteroids

Purpose

To study the role of Th₂-attracting chemokines in opsoclonus-myoclonus syndrome (OMS), a serious neurological paraneoplastic disorder in need of better immunological understanding and therapy.

Methods

The CCR4 agonists CCL22 and CCL17 were measured in serum by ELISA in children with OMS (238 and 260, respectively), pediatric controls (115 and 143), and other inflammatory neurological disorders (33 and 24).

Results

Both CCL22 (+55 %) and CCL17 (+121 %) were significantly elevated in untreated OMS compared to controls and inter-correlated (p?<?0.0001). Their concentrations in untreated OMS also were higher than in OIND (21 %, 41 %). The concentration of CCL22 in ACTH and steroids groups (not IVIg) was 51 % lower than in controls, but only a smaller effect of ACTH on CCL17 was found. Prospective longitudinal studies revealed a precipitous 81 % drop in CCL22 even by the first week of high-dose ACTH therapy, staying below control mean for at least 12 weeks, and a 34 % reduction after 8 months of combined treatment. Response to ACTH was dose-related (r?=??0.50, p?<?0.0001). Luminex detection confirmed the ELISA results for CCL22, which were about 200 % higher.

Conclusions

These data reveal an elevated serum concentration of Th₂-attracting chemokines CCL22 and CCL17 in OMS. Marked and rapid reduction in CCL22, not CCL17, with either ACTH or steroid therapy suggests differential regulation and cellular sources of CCR4 ligands, and CCL22 as a potential candidate biomarker for ACTH or corticosteroid effect.     

Anti-inflammatory and anti-arthritic activities of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (β-lapachone)

Objective and design

The purpose of this study was to evaluate the anti-inflammatory and anti-arthritic activities of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (β-lapachone; β-lap) and to elucidate its probable mode of action.

Methods

Carrageenan-induced paw edema, cell migration evaluation and production of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide were used for this study. Freund’s complete adjuvant (FCA)-induced arthritis was used as a model of chronic inflammation. β-Lap was tested in doses of 40 and 60 mg/kg, orally.

Results

In the paw edema test, the dose of 60 mg/kg gave a higher percentage inhibition of edema (49.3 %) than control. β-Lap inhibited neutrophil migration and reduced concentrations of TNF-α, IL-6 and NO in peritoneal exudates of animals with peritonitis. In the arthritis test, β-lap inhibited edema and NO production in the serum of treated animals.

Conclusion

Significant anti-inflammatory and anti-arthritic activities were observed in animals treated with β-lap. The effects of β-lap can be attributed in part to immunomodulation with reduction of pro-inflammatory cytokines and NO.     

Inflammatory Models

Objective and design

The sigma 1 (σ₁) receptor, which is widely distributed in the CNS in areas that are known to be important for pain control, may play a role in persistent pain characterized by the hypersensitivity of nociceptive transmission. Here, we investigated the effect of σ₁ blockade in an inflammatory pain model.

Treatment and methods

An intraplantar injection of carrageenan (2 %) was used to induce paw inflammation. The effects of the σ₁ antagonist (+)-MR200, given subcutaneously at a dose of 0.1, 0.25, 0.5,1, 1.5, and 2 mg/kg prior to injection of carrageenan, on inflammatory pain and inflammation were assessed. Mechanical allodynia with von Frey filaments, thermal hyperalgesia with the plantar test and edema evaluation with a plethysmometer were measured. Intergroup comparisons were assessed by one- or two-way analysis of variance when appropriate, followed by post-hoc tests (Dunnett’s test for one-way or Bonferroni for two-way ANOVA).

Results

(+)-MR200 dose-dependently prevented allodynia and hyperalgesia induced by carrageenan. Furthermore, it reduced paw edema with a significant inhibition percentage of 37.82 % at 3 h after carrageenan treatment.

Conclusions

The blockade of the σ₁ receptor with the selective antagonist (+)-MR200 may contribute to the suppression of the typical symptoms of inflammatory pain.     

Resveratrol alleviates inflammatory hyperalgesia by modulation of reactive oxygen species (ROS), antioxidant enzymes and ERK activation

Objectives

Impact of ROS in development of hyperalgesia has recently motivated scientists to focus on ROS as novel target of anti-hyperalgesic interventions. However, role of ROS in molecular signaling of hyperalgesia is still poorly understood. The present study is aimed to analyze the effect of dietary antioxidant resveratrol on antioxidant defense system, ROS level and TNFR1–ERK signaling pathway during early and late phase of inflammatory hyperalgesia.

Methods and materials

Hyperalgesia was assessed by paw withdrawal latency test in complete Freund’s adjuvant-induced hyperalgesic rats. Activities of antioxidant enzymes were measured by in-gel assays, ROS level was measured by DCFH₂DA, and expression of pERK, ERK and TNFR1 was estimated by Western blotting.

Results

Anti-hyperalgesic effect of resveratrol was observed by paw withdrawal latency test. ROS level was increased in paw skin as well as spinal cord during early phase which was further increased in paw skin, but remained constant in spinal cord up to late phase. Resveratrol differentially regulated the activities of SOD, catalase and GPx in paw skin as well as spinal cord of hyperalgesic rats in both phases. Activities were normalized back showing anti-hyperalgesic effect of resveratrol. Upregulated ERK signaling was modulated by resveratrol, whereas TNFR1 level remained unchanged.

Conclusion

Overall results suggest that resveratrol alleviates inflammatory hyperalgesia by downregulation of ERK activation, modulation of ROS and differential regulation of antioxidant enzymes during early and late phases.

     

Temporal changes in innate immune signals in a rat model of alcohol withdrawal in emotional and cardiorespiratory homeostatic nuclei

Background

Prokineticin 2 (PK2) is a secreted protein and causes potent hyperalgesia in vivo, and is therefore considered to be a new pronociceptive mediator. However, the molecular targets responsible for the pronociceptive effects of PK2 are still poorly understood. Here, we have found that PK2 potentiates the activity of acid-sensing ion channels in the primary sensory neurons.

Methods

In the present study, experiments were performed on neurons freshly isolated from rat dorsal root ganglion by using whole-cell patch clamp and voltage-clamp recording techniques.

Results

PK2 dose-dependently enhanced proton-gated currents with an EC₅₀ of 0.22?±?0.06 nM. PK2 shifted the proton concentration-response curve upwards, with a 1.81?±?0.11 fold increase of the maximal current response. PK2 enhancing effect on proton-gated currents was completely blocked by PK2 receptor antagonist. The potentiation was also abolished by intracellular dialysis of GF109203X, a protein kinase C inhibitor, or FSC-231, a protein interacting with C-kinase 1 inhibitor. Moreover, PK2 enhanced the acid-evoked membrane excitability of rat dorsal root ganglion neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, PK2 exacerbated nociceptive responses to the injection of acetic acid in rats.

Conclusion

These results suggest that PK2 increases the activity of acid-sensing ion channels via the PK2 receptor and protein kinase C-dependent signal pathways in rat primary sensory neurons. Our findings support that PK2 is a proalgesic factor and its signaling likely contributes to acidosis-evoked pain by sensitizing acid-sensing ion channels.     

Sulfated polysaccharides isolated from the green seaweed Caulerpa racemosa plays antinociceptive and anti-inflammatory activities in a way dependent on HO-1 pathway activation

Objective

Marine algae are abundant sources of sulfated polysaccharides with various biological activities. Consequently, their biomolecules are of great of commercial interest. In this study, we investigated the potential antinociceptive activity of a sulfated polysaccharide obtained from the green seaweed Caulerpa racemosa (CrII) and the involvement of the hemoxigenase-1 (HO-1) pathway in its anti-inflammatory effect.

Methods

We used a systemic evaluation to verify possible toxic effects of Crll after consecutive treatments. Swiss mice and Wistar rats were used for all experiments.

Results

In Swiss mice, CrII (0.01, 0.1 and 1.0 mg/kg) significantly reduced the number of abdominal contortions and the duration of paw licking in the second phase after treatment with acetic acid and formalin, respectively. However, CrII was unable to prolong the reaction time of thermally stimulated animals. The anti-inflammatory effect of CrII (0.01, 0.1 and 1.0 mg/kg) was evidenced by a decreased number of leukocytes in the peritoneal cavities of the rats. CrII (0.01, 0.1 and 1.0 mg/kg) also reduced the amount of paw edema induced by carrageenan (Cg) and dextran. The anti-inflammatory effect of CrII was confirmed by reduced levels of myeloperoxidase in the paw tissue of the Cg groups. After inhibition with ZnPP IX, a specific HO-1 phenotype inhibitor, the anti-inflammatory effect of CrII was no longer observed in Cg-induced paw edema tests. Consecutive Crll (1.0 mg/kg) for 14 days did not change any biochemical or histopathological parameters, or cause mortality of mice.

Conclusions

CrII did not produce any signs of toxicity and effectively decreased nociception and inflammation. Also, the anti-inflammatory effect of Crll is at least in part dependent on the integrity of the HO-1 pathway.     

Protective effects and potential mechanisms of Pien Tze Huang on cerebral chronic ischemia and hypertensive stroke

Background

Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH), a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats.

Methods

The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR) and stroke prone SHR (SHRsp) were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA) and immunostaining.

Results

Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCR₂ in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS) damage and possibly subsequent cell death (caspase 3 assay) as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum.

Conclusion

Pien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria.     

Changes in contractile and elastic properties of the triceps surae muscle induced by neuromuscular electrical stimulation training

Purpose

Neuromuscular electrical stimulation (NMES) training is known to induce improvement in force production capacities and fibre-type transition. The aim of this study was to determine whether NMES training also leads to changes in the mechanical properties of the human triceps surae (TS) muscle.

Methods

Fifteen young male subjects performed a training protocol (4 weeks, 18 sessions, 4–5 sessions per week) based on a high-frequency isometric NMES programme of TS muscle. Quick-release test was used to evaluate Musculo-Tendinous (MT) stiffness index (SI_MT) as the slope of the linear MT stiffness–torque relationships under submaximal contraction. Sinusoidal perturbations allowed the assessment of musculo-articular stiffness index (SI_MA) as well as the calculation of the maximal angular velocity ( \(\varTheta_{\hbox{max} }^{{\prime }}\) ) of TS muscle using an adaptation of Hill’s equation.

Results

After NMES training, Maximal Voluntary Contraction under isometric conditions and \(\varTheta_{\hbox{max} }^{{\prime }}\) increased significantly by 17.5 and 20.6 %, respectively, while SI_MT and SI_MA decreased significantly (?12.7 and ?9.3 %, respectively).

Conclusions

These changes in contractile and elastic properties may lead to functional changes of particular interest in sport-related activities as well as in the elderly.     

Thermal perceptions and skin temperatures during continuous and intermittent ventilation of the torso throughout and after exercise in the heat

Objective

This study tested the hypothesis that intermittent cooling in air-perfused vests (APV) will not only maintain thermal balance but, due to cyclical activations of cutaneous thermoreceptors, also enhance thermal perceptions.

Method

Ten physically active males completed four conditions where they exercised (walking: 5 km h^?1, 2 % gradient) in a hot environment (~34.0 °C, 50 % RH) for 72 min, followed by a 33-min period of rest. They wore an APV throughout. The four conditions differed in respect to the profile of ambient air that was perfused through the APV: continuous perfusion (CP); intermittent perfusion of 6 min ON/OFF periods (IP_onoff); a steady increase and decrease in flow rate in equal increments (IP_ramp); and an initial step-increase in the flow rate followed by an incremental decrease to zero flow rate (IP_triang). Whole body and torso thermal comfort (TC, TTC), whole body and torso temperature sensation (TS, TTS), whole body and torso skin temperature ( $\bar{T}_{\text{sk}}$ , $\bar{T}_{\text{sktorso}}$ ), local relative humidity ( $\overline{RH}_{\text{torso}}$ ) and rectal temperature (T _re) were measured.

Results

There were no significant differences in T _re, absolute whole body and local $\bar{T}_{\text{sk}}$ , TC, TTC and TS between the cooling profiles. However, TTS was cooler in CP and IP_ramp than IP_onoff and IP_triang. Even though intermittent cooling did not significantly enhance thermal perceptions in CP, a trend existed for TC (P = 0.063) to become less favourable over time.

Conclusion

To reduce the power consumption and extend the battery life of an APV, it is recommended that an intermittent cooling profile should be adopted.