Metabolic profiling studies on the toxicological effects of realgar in rats by H NMR spectroscopy

The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of ¹H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. ¹H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.     

The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: A novel pain modulation pathway

Recently, a series of studies have given rise to and provided evidence for the hypothesis that the nucleus submedius (Sm) in the medial thalamus is involved in modulation of nociception. The Sm, ventrolateral orbital cortex (VLO) and the periaqueductal gray (PAG) constitute a pain modulatory pathway, activation of which leads to activation of the PAG–brainstem descending inhibitory system and depression of the nociceptive inputs in the spinal cord and trigeminal nucleus. Other studies have indicated that the Sm–VLO–PAG pathway plays an important role in the analgesia induced by electroacupuncture stimulation of the acupuncture point (acupoint) for exciting small diameter fiber (A-δ and C group) afferents. Opioid peptides, serotonin, dopamine, glutamate and their related receptors are involved in Sm- and/or VLO-mediated descending antinociception, and a GABAergic disinhibitory mechanism participates in mediating the antinociception induced by activation of μ-opioid receptors, serotonin 1_A receptors, and dopamine D₂-like receptors. This review describes these findings, which provide important new insights into the roles of the thalamus and cerebral cortex in descending pain modulation.     

Stress-induced analgesia

For over 30 years, scientists have been investigating the phenomenon of pain suppression upon exposure to unconditioned or conditioned stressful stimuli, commonly known as stress-induced analgesia. These studies have revealed that individual sensitivity to stress-induced analgesia can vary greatly and that this sensitivity is coupled to many different phenotypes including the degree of opioid sensitivity and startle response. Furthermore, stress-induced analgesia is influenced by age, gender, and prior experience to stressful, painful, or other environmental stimuli. Stress-induced analgesia is mediated by activation of the descending inhibitory pain pathway. Pharmacological and neurochemical studies have demonstrated involvement of a large number of neurotransmitters and neuropeptides. In particular, there are key roles for the endogenous opioid, monoamine, cannabinoid, γ-aminobutyric acid and glutamate systems. The study of stress-induced analgesia has enhanced our understanding of the fundamental physiology of pain and stress and can be a useful approach for uncovering new therapeutic targets for the treatment of pain and stress-related disorders.     

Central representation of cold-evoked pain relief in capsaicin induced pain: an event-related fMRI study

The termination of an unpleasant or painful somatic condition can produce a rewarding sense of relief, even if the stimulus that causes the termination is itself unpleasant or painful under normal circumstances. We aimed to identify central neural mechanisms of pain relief from capsaicin-elicited heat-hyperalgesia by administering cold stimuli. We hypothesized that cooling might facilitate endogenous descending inhibitory mechanisms. We compared intraindividual neural responses of 15 healthy male volunteers to cold (20, 0 degrees C), intermediate (30 degrees C) and heat stimuli (43 degrees C) on untreated vs. capsaicin-treated skin using event-related fMRI in a 2 x 4 factorial design. Thermal stimuli were applied at the right hand in two separate imaging sessions using a Peltier-element. Psychophysical ratings of the perceived valence and intensity (VAS: 1-100) were obtained after each stimulus. The 43 degrees C-stimulus was perceived as excessively painful on capsaicin-treated skin as opposed to an unpleasant sensation on normal skin. In contrast, the 0 degrees C-stimulus was perceived unpleasant when applied on untreated skin while subjects rated the same stimulus pleasant in the capsaicin-treated condition. When neural responses to the 0 degrees C-stimulus were compared between the untreated and capsaicin-treated skin condition there were stronger BOLD-responses in prefrontal cortex (PFC) and periaqueductal grey (PAG) which correlated with increasing perceived pleasantness (VAS). Based on a connectivity analysis which identified cold-dependent contributions of PFC activity with PAG in heat-hyperalgesia we propose that cold-induced pain relief partly results from activation of endogenous descending inhibition of nociception. The data illustrate that perception of nociceptive input may largely be determined by competing aversive-appetitive motivational states.     

Pregnancy-associated glycoprotein (PAG) family localized in chorionic cells within the epitheliochorial/diffuse placenta of the alpaca (Lama pacos)

Pregnancy-associated glycoproteins (PAGs) are abundant embryo-originated products expressed in the pre-placental trophoblast and later in the post-implantational chorionic epithelium of some ungulate species. This paper describes the cellular immunolocalization of the chorionic PAG family in the epitheliochorial placenta type of the alpaca (Lama pacos—Lp), in which the PAGs were named ‘LpPAGs’. Placental Lp sections (5 μm) of different females near mid-pregnancy (150 days post coitum; dpc), advanced pregnancy (244-263 dpc) and late pregnancy (347 dpc) were used for cross-species (heterologous—ht) double fluorescent immunohistochemistry (htdF-IHC). The htdF-IHC was performed with primary rabbit polyvalent anti-porcine PAG polyclonals. The LpPAG immuno-complexes were visualized with secondary goat anti-rabbit immunoglobulins-conjugated with Alexa 488 fluorophore (green), among all nuclei of placental cells stained with propidium iodide (red). This is the first study reporting the immunolocalization of the LpPAG family identified by htdF-IHC at the feto/maternal interface during different pregnancy stages of the alpaca. The most dominant and strongest immune-positive LpPAG signals were found in the well-developed chorionic cell layer. Our htdF-IHC indicated relatively high epitope resemblance to that of the PAGs in camelids and pigs. These data increase our general knowledge of chorionic PAG localization during pregnancy-stage dependent development of the epitheliochorial diffuse placenta type in the alpaca.     

Expression of pregnancy-associated glycoprotein family in the epitheliochorial placenta of two Camelidae species (C. dromedarius and C. bactrianus)

This study describes placental morphology and immunolocalization of the placental pregnancy associated glycoprotein-like family (PAGs) identified in two selected taxa of Old-World camels of the Camelidae family: Camelus dromedarius (Cd) and Camelus bactrianus (Cb). Placental tissues of Cd from days 140–293 post-coitum (dpc), term (404 dpc); and of Cb from term (440 dpc) were examined. Histological staining (hematoxylin/eosin and propidium iodine) revealed the development of the placental structure, while chorionic folding increased the feto-placental surface during the progress of pregnancy. The camelid placenta during early pregnancy is similar to the diffuse epitheliochorial type, and during later stages of pregnancy resembles the synepitheliochorial (cotyledonary) type. Placental expression of the PAGs was detected (Alexa 488 – green) within camelid trophectoderm cells (TRD – chorionic epithelium as outer layer of embryonic cells) among all placental cells with nuclei stained by propidium iodide (red). The PAGs, identified in both Camelidae taxa, were named CbPAGs and CdPAGs. Placental CbPAG and CdPAG expression is restricted to the TRD cells, which are differentially developed throughout gestation. Cross-reactivity of polyvalent anti-pPAG polyclonals with the CbPAGs and CdPAGs revealed high structural similarities of the PAG-like epitopes in pigs and camels. This is the first study identifying PAG expression in chorionic cells of the camel placenta.     

阿斯匹林抗血栓的实验室监测与临床效应的初步研究

目的：研究血栓患者在服用阿斯匹林后的实验室监测指标。方法：研究了44例每日服用300mg阿斯匹林的血栓患者和20例正常人，观察其血小板聚集率（PAG）、凝血酶原时间（PT）、凝血酶时间（TT）以及活化的部分凝血活酶时间（KPTT）的变化。结果：阿斯匹林引起TT的改变有显著性差异。结论：TT可以作为血栓病患者在服用300mg/日阿斯匹林后实验室监测的一个重要指标。     

Electrophysiological analysis of midbrain periaqueductal gray influence on cardiovascular neurons in the ventrolateral medulla oblongata

Stimulation of sites in the rostral or caudoventral periaqueductal gray (PAG) results in substantial increases in mean blood pressure (MBP) and heart rate (HR). The efferent pathways from these PAG subregions possibly include a relay in the ventrolateral medulla oblongata (VLM), where neurons involved in maintaining vasomotor tone are located. Extracellular recordings were made from 21 cardiovascular neurons in the rostral VLM (RVLM) and from 6 cardiovascular neurons in the caudal VLM (CVLM) of the rat. These neurons showed barosensitivity and cardiac rhythmicity. In addition, the activity of 54 noncardiovascular and nonrespiratory units was recorded. Responses to electrical stimulation of sites in the (rostral or caudal) PAG were studied in 16 of the 21 cardiovascular RVLM neurons, the 6 CVLM neurons, and 46 of the 54 noncardiovascular neurons. Eight of the RVLM neurons were excited by rostral PAG stimulation; the poststimulus time histograms showed a constant latency in five units (32 ± 3 ms). This suggests the presence of relatively direct (although not monosynaptic) excitatory pathways from the rostral PAG to cardiovascular neurons in the RVLM, consisting of slowly conducting fibers (0.2-0.3 m/s). Five RVLM neurons did not respond to rostral PAG stimulation. Three units were tested with caudal PAG stimulation: one was excited, one inhibited, and one was unresponsive. The six cardiovascular CVLM neurons did not respond to PAG stimulation. Of the 46 noncardiovascular neurons, 14 cells were excited, 7 inhibited, and 2 cells antidromically activated. These results confirm earlier findings, extending them to the rostral PAG. They supply further evidence for the influence of the PAG on the cardiovascular function-related neuronal circuitry in the VLM.