Activation of adenosine A3 receptor inhibits inflammatory cytokine production in colonic mucosa of patients with ulcerative colitis by down-regulating the nuclear factor-kappa B signaling.

OBJECTIVES: The activation of the adenosine A3 receptor (A3AR) can regulate inflammation, but the way that this regulates colonic mucosal inflammation in ulcerative colitis (UC) remains unclear. This study aimed at examining A3AR expression and investigating the effect of A3AR activation on ex vivo cytokine expression and nuclear factor-kappa B (NF-κB) signaling in colonic mucosa. METHODS: Colonic mucosal biopsied tissue from 18 patients with UC and 11 healthy controls was tested for A3AR expression by immunofluorescence, quantitative real-time polymerase chain reaction and Western blot. Following treatment for 24 hours with or without 2-Cl-IB-MECA, an A3AR agonist, TNF-α and IL-1ß secreted by the cultured colonic mucosal tissue were quantified by ELISA. The colonic mucosal epithelia were dissected and treated with, or without 2-Cl-IB-MECA for 24 hours. The NF-κB p65 protein and its distribution in the cultured colonic epithelia were examined by immunofluorescence and Western blot. RESULTS: Compared with the controls, down-regulated A3AR expression and up-regulated TNF-α and IL-1ß production and NF-κB p65 protein were observed in the UC colonic mucosa. The activation of A3AR by 2-Cl-IB-MECA significantly decreased TNF-α and IL-1ß production and attenuated the NF-κB p65 activation in colonic tissues from patients with UC. CONCLUSIONS: A3AR activation inhibited inflammation by mitigating pro-inflammatory cytokine production and the NF-κB signal activation in colonic mucosa of patients with UC. A3AR activation may play a role in the pathogenesis of UC.

Gastrointestinal bleeding after intracerebral hemorrhage: a retrospective review of 808 cases.

BACKGROUND: This study examined the incidence and risk factors for gastrointestinal (GI) bleeding after spontaneous intracerebral hemorrhage (ICH). METHODS: The available medical records of patients with ICH admitted from June 2008 to December 2009 for any episode of GI bleeding, possible precipitating factors and administration of ulcer prophylaxis were reviewed. RESULTS: The prevalence of GI bleeding was 26.7%, including 3 cases of severe GI bleeding (0.35%). Patients with GI bleeding had significantly longer hospital stay and higher in-hospital mortality compared with patients without GI bleeding. Multivariate logistic regression analyses showed that age, Glasgow Coma Scale scores, sepsis and ICH volume were independent predictors of GI bleeding. About 63.4% of patients with ICH received stress ulcer prophylaxis. CONCLUSIONS: GI bleeding occurred frequently after ICH, but severe events were rare. Age, Glasgow Coma Scale score, sepsis and ICH volume were independent predictors of GI bleeding occurring after ICH.

Clinical pharmacology considerations in biologics development.

Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.

Gynura root induces hepatic veno-occlusive disease: a case report and review of the literature.

Gynura root has been used extensively in Chinese folk medicine and plays a role in promoting microcirculation and relieving pain. However, its hepatic toxicity should not be neglected. Recently, we admitted a 62-year old female who developed hepatic veno-occlusive disease (HVOD) after ingestion of Gynura root. Only a few articles on HVOD induced by Gynura root have been reported in the literature. It is suspected that pyrrolizidine alkaloids in Gynura root might be responsible for HVOD. In this paper, we report a case of HVOD and review the literature.

Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome.

Early life stress has been implicated as a risk factor for irritable bowel syndrome (IBS). We studied the effect of neonatal maternal separation on the visceromotor response and the expression of c-fos, 5-HT, and its receptors/transporters along the brain-gut axis in an animal model of IBS. Male neonatal Sprague-Dawley rats were randomly assigned to a 3-h daily maternal separation (MS) or nonhandling (NH) on postnatal days 2-21. Colorectal balloon distention (CRD) was performed for assessment of abdominal withdrawal reflex as a surrogate marker of visceral pain. Tissues from dorsal raphe nucleus in midbrain, lumbar-sacral cord, and distal colon were harvested for semiquantitative analysis of c-fos and 5-HT. The expression of 5-HT expression, 5-HT3 receptors, and 5-HT transporter were analyzed by RT-PCR. Pain threshold was significantly lower in MS than NH rats. The abdominal withdrawal reflex score in response to CRD in MS rats was significantly higher with distension pressures of 40, 60, and 80 mmHg. In MS rats, the number of c-fos-like immunoreactive nuclei at dorsal horn of lumbar-sacral spinal cord increased significantly after CRD. 5-HT content in the spinal cord of MS rats was significant higher. In the colon, both 5-HT-positive cell number and 5-HT content were comparable between MS and NH groups before CRD. Post-CRD only MS rats had significant increase in 5-HT content. Protein and mRNA expression levels of 5-HT3 receptors and 5-HT transporter were similar in MS and NH rats. Neonatal maternal separation stress predisposes rats to exaggerated neurochemical responses and visceral hyperalgesia in colon mimicking IBS.

[Effect of ligustrazine on bone marrow hematopoiesis in mice after bone marrow transplantation].

OBJECTIVE: To investigate the effect of ligustrazine (LT) on hematopoiesis in mice after bone marrow isotransplantation (iso-BMT). METHODS: The typical model of iso-BMT was established and the model mice were randomly divided into two groups, the LT group treated with LT injection 0.2 ml and the control group treated with normal saline 0.2 ml, twice a day by gastrogavage. The following parameters were observed in the day 1, 7 and 14: peripheral blood cells, bone marrow mono-nuclear cells (BMMNC), heparin sulfate (HS) expression in bone marrow section by immunohistochemical SABC-AP method, stromal cell derived factor-1 (SDF-1) expression and CXC chemotaxis factor receptor 4 (CXCR4) expression. RESULTS: The levels of peripheral WBC, platelet, BMMNC, CXCR4, HS, SDF-1 at the day 7 and 14 in the LT group were all higher significantly than those in the control group (P < 0.05 or P < 0.01). CONCLUSION: LT could improve the bone marrow hematopoiesis in the early hematopoietic re-establishing stage after BMT.