Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Tanshinone IIA alleviates lipopolysaccharide-induced acute lung injury by downregulating TRPM7 and pro-inflammatory factors.

The study aimed to investigate the role of Tanshinone IIA (Tan IIA) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in its regulation of TRPM7. Wistar male rats were randomly divided into the normal saline (NS), LPS, knockout (KO) + LPS, low-dose Tan IIA (Tan-L), middle-dose Tan IIA (Tan-M), high-dose Tan IIA (Tan-H) and KO + high-dose Tan IIA (KO + Tan-H) groups. The level of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, TRPM7 protein expression, current density-voltage curve and Ca2+ concentration were detected through ELISA, Western blotting, electrophysiological experiment and a calcium-imaging technique, respectively. The rats in the KO + LPS, Tan-L, Tan-M, Tan-H and KO + Tan-H groups all displayed lower levels of TNF-α, IL-1ß and IL-6 than the LPS group. Rats in the KO + Tan-H group exhibited lower levels of NF-α, IL-1ß and IL-6 than rats in the Tan-H group. Elevated levels of TRPM7 protein expression in the LPS and Tan groups were detected in comparison with the NS group. However, TRPM7 protein expression in Tan-M and Tan-H groups was notably lower than in that of the LPS group. In comparison with the NS group, the LPS and Tan groups had a greater PIMs cell density and a higher concentration of Ca2+ . Contrary results were observed in the KO + LPS, Tan-H and KO + Tan-H groups. Tan IIA decreases calcium influx in PIMs and inhibits pro-inflammatory factors which provide an alleviatory effect in regards to LPS-induced ALI by suppressing TRPM7 expression.

New insights on the role of the insular cortex and habenula in OSA.

PURPOSE: Abnormal structure or function in the central nervous system (CNS) can also affect obstructive sleep apnea (OSA). Because human afferent and motor pathways that regulate apnea are still poorly understood, it is not possible to modify the behavior of motor neurons to control airway function. The purpose of this article is to clear the central control mechanism of genioglossus (GG) and to discuss how altered activity in the limbic system and its related structures might affect OSA development, in order to provide help for the treatment of this disease. METHODS: Functional magnetic resonance imaging (fMRI) data from previous studies on OSA-related brain damage in human beings plus the data from clinical and animal experiments are summarized. These articles are overviewed to discuss the roles of the limbic system-the insular cortex (Ic), the habenula (Hb), and CNS-in the pathogenesis and mechanisms of OSA. RESULTS: The Ic, which relays signals through the Hb, may play a role in OSA because activating the Ic causes the Hb to suppress activity of the raphe nucleus (RN), resulting in lower levels of 5-hydroxytryptamine (5-HT) that decreases the muscle tone of the GG. This leads to airway collapse. CONCLUSIONS: The Ic may be an important region in the development of OSA. Altered activity in the limbic system and its related structures could also be associated with OSA.

Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage.

Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca2+-dependent brain injury.

Injection of L-glutamate into the insular cortex produces sleep apnea and serotonin reduction in rats.

PURPOSE: Obstructive sleep apnea (OSA) is primarily characterized by repetitive episodes of complete or partial obstruction of airflow during sleep. The neuronal and cellular mechanisms underlying this process are not fully understood, although the focus of some studies is on putative serotonin (5-HT) mechanisms, and serotonergic therapy may be beneficial to OSA patients. This study aimed to demonstrate possible changes in 5-HT associated with induction of OSA in a rat model. METHODS: Apnea was induced in rats by injection of L-glutamate (L-Glu) into the insular cortex. We examined changes in: (1) simultaneous genioglossus and diaphragm EMG activity; and (2) peripheral and cerebral levels of 5-HT, by histology. RESULTS: Injection of L-glutamate (L-Glu) into the insular cortex induced apnea in the rats. L-Glu stimulation of the insular cortex also produced significant reductions in plasma 5-HT levels and the expression of 5-HT in the brainstem. In addition, lower activity was observed in the GG and a higher activity was observed in the diaphragm, as compared to controls. CONCLUSION: Data indicate that L-Glu stimulation of the insular cortex simulates the electrical activity of the genioglossus muscle and diaphragm in sleep apnea, and contributes to reduced peripheral and cerebral 5-HT levels in rats. The results of our study suggest that 5-HT may play a role in the pathogenesis of OSA.

Mal-effects of obstructive sleep apnea on the heart.

OBJECTIVE: This study aims to examine the impact of chronic intermittent hypoxia on hearts in patients with obstructive sleep apnea (OSA). METHODS: Two hundred twenty patients were divided into groups based on (1) severity of the disease, (2) years of disease history, and (3) with or without secondary hypertension. All subjects underwent blood pressure measurements, polysomnogram monitoring, and cardiac Doppler ultrasound examinations. RESULTS: The left ventricular ejection fraction (LVEF), fractional shortening (FS), and the ratio of early to late diastolic filling (E/A) in patients with severe OSA were lower than in those with moderate OSA and in healthy controls. The inner diameters of the main pulmonary artery (inD of MPA), the inner diameters of the right cardiac ventricle (inD of RV), and the thickness of anterior wall of the right ventricle (TAW of RV) were increased in patients with severe OSA compared to those with moderate disease and worsened as a function of time with disease. The tissue Doppler imaging-derived Tei index and pulmonary artery systolic pressure were also increased along with the severity of OSA. LVEF and FS in patients who had suffered from OSA for >10 years were decreased compared with those suffering from OSA for a shorter time. LVEF and FS in patients with secondary hypertension were decreased significantly relative to non-hypertensive OSA patients and healthy controls. E/A was decreased in OSA patients whether they had secondary hypertension or not. CONCLUSION: OSA affected the left ventricular diastolic function in the early stage of the disease. Extended exposure to OSA resulted in left ventricular dysfunction with increased hypertension. Right ventricle dysfunction and abnormalities became more severe as the disease progressed.

Electroencephalography Microstate Alterations in Otogenic Vertigo: A Potential Disease Marker.

Objectives: A huge population, especially the elderly, suffers from otogenic vertigo. However, the multi-modal vestibular network changes, secondary to periphery vestibular dysfunction, have not been fully elucidated. We aim to identify potential microstate electroencephalography (EEG) signatures for otogenic vertigo in this study. Materials and Methods: Patients with recurrent otogenic vertigo and age-matched healthy adults were recruited. We performed 256-channel EEG recording of all participants at resting state. Neuropsychological questionnaires and vestibular function tests were taken as a measurement of patients' symptoms and severity. We clustered microstates into four classes (A, B, C, and D) and identified their dynamic and syntax alterations of them. These features were further fed into a support vector machine (SVM) classifier to identify microstate signatures for vertigo. Results: We compared 40 patients to 45 healthy adults, finding an increase in the duration of Microstate A, and both the occurrence and time coverage of Microstate D. The coverage and occurrence of Microstate C decreased significantly, and the probabilities of non-random transitions between Microstate A and D, as well as Microstate B and C, also changed. To distinguish the patients, the SVM classifier, which is built based on these features, got a balanced accuracy of 0.79 with a sensitivity of 0.78 and a specificity of 0.8. Conclusion: There are several temporal dynamic alterations of EEG microstates in patients with otogenic vertigo, especially in Microstate D, reflecting the underlying process of visual-vestibular reorganization and attention redistribution. This neurophysiological signature of microstates could be used to identify patients with vertigo in the future.

[The observation of the influence about blood pressure and cardiovascular B ultrasonic wave by chronic intermittent hypoxia].

OBJECTIVE: To investigate the influence of left heart function in obstructive sleep apnea by CIH, and explore left heart function and blood pressures before or after CPAP. METHODS: 75 OSA were divided into two groups: 40 patients blood pressures were coincident with diagnostic standard of hypertension recording; 35 patients blood pressures were non-hypertension recording. The control group included 30. healthy adults. The blood pressures before and also after sleep, left ventricular ejection fraction (LVEF), shortening fraction (FS), E, A and E/A were compared with those of normal control subjects. Analyzed BP, LVEF and E/A after CPAP. RESULTS: (1) The blood pressure soon after getting up in the morning (150.80+/-20.73/108.0+/-15.34) mm Hg (1 mm Hg=0.133 kPa) was significantly higher than that before sleep (134.16+/-18.33/90.09+/-11.24) mm Hg (P<0.001). (2) Multiple parameters including LVEF, FS and E/A, were impaired in OSA patients relative to the control subjects (P<0.05 or P<0.01), OSA affected cardiovascular function directly; E/A was significantly decreased in obstructive sleep apnea unallied hypertension than that in normal control subjects; E/A was conspicuously decreased in obstructive sleep apnea associated hypertension comparing with that in obstructive sleep apnea unallied hypertension. These showed OSA affected cardiovascular function directly, hypertension aggravated the drop in cardiovascular function. 3. After CPAP in 6 months, it (142.59+/-15.34/96.52+/-9.81) mm Hg was significantly decreased than that before treatment (150.80+/-20.73/108.0+/-15.34) (P<0.001); LVEF (59.70+/-11.1)% was increased than that before treatment (56.40+/-9.74)% (P<0.05) and E/A 1.16+/-0.25 was increased. Than that before treatment 0.87+/-0.17 (P<0.01). CONCLUSION: (1) CIH may affect left heart structure and function; these changes were aggravated with hypertension. (2) CPAP treatment had important sense in the treatment of hypertension and cardiovascular function, and improved the life quality.

Modulatory effect of Tim-3/Galectin-9 axis on T-cell-mediated immunity in pulmonary tuberculosis.

Patients affected by pulmonary tuberculosis (PTB) manifest deficiencies in innate cellular immunity. The Tim3/Galectin-9 axis is an important regulator of Th1 cell immunity, leading to Th1 cell apoptosis. Herein, this study aims to clarify the underlying roles of the Tim-3/Galectin-9 axis in T-cell immunity in PTB. Peripheral blood mononuclear cells (PBMCs) were extracted from subjects with and without PTB to examine the expression of CD4, CD8, CD25, and Tim-3 under the stimulation of Mycobacterium tuberculosis (MTB) and purified protein derivative (PPD). In addition, the expression of Tim-3 and Galectin-9 in PBMCs was determined. The Tim-3/Galectin-9 axis in the PBMCs was activated or blocked to detect the secreted levels of IFN-γ, TNF-α, IL-2, and IL-22. MTB stimulation increased the expression of CD4, CD8, CD25, Tim-3, and Galectin-9 in PBMCs. The blockade of Tim-3/Galectin-9 axis resulted in reduced secretion of IFN-γ, TNF-α, IL-2, and IL-22 from T-cells. Moreover, Tim-3+CD4+T, Tim-3+CD8+, and Tim-3+CD25+T cells exhibited a greater ability to inhibit the replication of MTB in macrophages. Taken conjointly, the blockade of Tim-3/ Galectin-9 axis inhibits the secretion of inflammatory cytokines in T-cells to regulate the T-cell immunity in PTB.

[Effects of obstructive sleep apnea-hypopnea syndrome upon cardiac structure and function].

OBJECTIVE: To investigate the effects of obstructive sleep apnea-hypopnea syndrome (OSAHS) upon cardiac structure and function of patients. METHODS: According to apnea hypopnea index, 75 OSAHS patients were divided into three groups: mild (n = 25), moderate (n = 25) and serious (n = 25); according to the course of disease, < 5 years (n = 22), 5-10 years (n = 26) and > 10 years (n = 27). The control group included 25 healthy adults. All subjects received polysomnogram and echocardiography. The following parameters were recorded: aortic dimension, pulmonary artery inner diameter, chambers heart size, interventricular septal thickness, anterior wall thickness and movement extent of end-diastole right ventricle, left ventricular ejection fraction (LVEF), shortening fraction (FS) and E/A ratio, etc. RESULTS: Pulmonary artery inner diameter of mild, moderate, serious and control groups were (21.4 +/- 2.5), (24.7 +/- 2.0), (26.7 +/- 2.1), (21.2 +/- 2.7) mm, right ventricle internal diameter (19.0 +/- 1.8), (22.0 +/- 2.1), (23.9 +/- 2.1), (18.9 +/- 1.8) mm, and anterior wall thickness of right ventricle (4.7 +/- 1.2), (6.5 +/- 1.3), (7.5 +/- 1.4), (4.1 +/- 1.0) mm. The moderate and serious groups were all higher than control and mild groups obviously (P < 0.01). The serious group was higher than the moderate group (P < 0.01). LVEF of four groups: (63.1 +/- 8.1)%, (60.0 +/- 10.2)%, (54.5 +/- 9.1)%, (63.6 +/- 7.7)%, FS: (38.1 +/- 4.3)%, (37.0 +/- 6.4)%, (33.6 +/- 5.4)%, (39.5 +/- 4.9)%, and E/A: (1.13 +/- 0.13), (0.96 +/- 0.16), (0.85 +/- 0.12), (1.28 +/- 0.15). LVEF and FS of the serious group were lower than those of the control, mild and moderate groups (P < 0.05). E/A ratio of the mild, moderate and serious groups were lower than the control group (P < 0.01). The interclass comparison of mild, moderate and serious groups had significant differences (P < 0.01). Right ventricle internal diameter, pulmonary artery inner diameter, anterior wall thickness of right ventricle of > 10 years group were higher than 5-10 years group obviously (P < 0.05, P < 0.01). The 5-10 years group was higher than the < 5 years and control groups obviously (P < 0.05, P < 0.01). LVEF, FS, and E/A ratio of > 10 years group were lower than 5-10 years, < 5 years and control groups obviously (P < 0.05, P < 0.01). CONCLUSION: OSAHS causes structural and functional cardiac changes worsening with disease aggravation and course extension.

Effects of Habenular Stimulation Frequencies on Obstructive Sleep Apnea Induced by Stimulation of Insular Cortex.

Objective: To investigate the effects of high-frequency stimulation of the habenula (Hb) on obstructive sleep apnea (OSA) induced by stimulation of the insular cortex Method. After OSA was induced by stimulating the insular cortex (Ic) with concentric stimulating electrodes at 100 Hz in rats, the Hb was stimulated at different frequencies (50 Hz, 120 Hz, 130 Hz, and 280 Hz). The changes of apnea events and electromyography (EMG) of the genioglossus were compared before and after stimulation of the Hb. Results: With stimulation of the Ic at 100 Hz, apnea events were successfully induced with disappearance of EMG of the genioglossus. After stimulation of the Hb at 130 Hz, apnea events disappeared with significantly increased genioglossal EMG. However, such a change failed to be found at the stimulation frequencies of 50 Hz, 120 Hz, and 280 Hz. Conclusion: Stimulation of the Hb at the frequency of 130 Hz could effectively inhibit OSA events induced by stimulation of the Ic.

Pro-inflammatory role of transient receptor potential canonical channel 6 in the pathogenesis of chronic rhinosinusitis with nasal polyps.

BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) has not been fully elucidated. This study sought to explore the role and mechanism of transient receptor potential canonical channel 6 (TRPC6) in the pathogenesis of CRSwNP. METHODS: Immunohistochemistry (IHC) was employed to evaluate TRPC6 immunolabeling. Real-time polymerase chain reaction (PCR) was conducted to assay TRPC6, stromal interaction molecule 1 (STIM1), and calcium release-activated calcium channel protein 1 (Orai1) messenger RNA (mRNA) levels in 70 patients with CRSwNP, including eosinophilic CRSwNP (ECRSwNP) or non-eosinophilic CRSwNP (nECRSwNP), and 28 control subjects. The concentrations of inflammatory mediators, including interleukin (IL)-1ß, IL-5, and IL-25, were assayed by enzyme-linked immunosorbent assay (ELISA). In experiments on human nasal epithelial cell (HNEC) culture and stimulation, the mean fluorescence intensity (MFI) of intracellular Ca2+ was assayed by flow cytometry. Western blotting, real-time PCR, and ELISA were also conducted to assess the effects and mechanisms of TRPC6 activator 1-oleoyl-2-acetyl-glycerol (OAG) and TRPC6 inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) on HNECs. RESULTS: Upregulation of TRPC6, STIM1, and Orai1 levels was found in CRSwNP patients, particularly in those with ECRSwNP. TRPC6-positive cells correlated positively with the numbers of eosinophils and neutrophils, respectively. Moreover, TRPC6 mRNA was positively correlated with STIM1 and Orai1 mRNA levels. The concentrations of inflammatory mediators, including IL-1ß, IL-5, and IL-25, were elevated in CRSwNP, especially in ECRSwNP. In cultured HNECs, TRPC6, STIM1, Orai1, Ca2+ MFI levels, and inflammatory mediators were upregulated by lipopolysaccharide (LPS) and OAG but were inhibited by SKF-96365. CONCLUSION: TRPC6 plays a pro-inflammatory role in the pathogenesis of CRSwNP via regulating Ca2+ flow.

[The prevalence of obstructive sleep apnea-hypopnea syndrome in adults aged over 20 years in Changchun city].

OBJECTIVE: To investigate the prevalence of obstructive sleep apnea-hypopnea syndrome (OSAHS) in adults aged over 20 years in Changchun city, providing epidemiological data for treatment and prevention of the disease. METHODS: 3,960 subjects were derived from a stratified cluster and random sampling of the population in two districts of Changchun city. They were asked to answer the questions from a questionnaire in their houses. According to the degree of snoring, 200 subjects with a snoring score >or= 2 degree were selected to undergo polysomnography for a whole night and the prevalence of the disease was estimated. RESULTS: A total of 3,648 (97.64%) validated questionnaires was collected. Of them 31.00% had a snoring score >or= 2 degree, the prevalence was higher in males (40.07%) than in females (21.76%). The prevalence of snoring was higher in drivers (42.47%) than in other occupations. The estimated prevalence of OSAHS defined by apnea-hypopnea index (AHI) >or= 5, Epworth sleepiness scale (ESS) >or= 9 and arterial oxygen saturation (SaO(2)) < 90% was 4.81%. CONCLUSIONS: The estimated prevalence of OSAHS in adults aged over 20 years in Changchun city was 4.81%. Doctors should pay more attention to the disease and the ordinary people should be informed of the health impact of snoring and OSAHS.

Is brain damage really involved in the pathogenesis of obstructive sleep apnea?

Obstructive sleep apnea (OSA) syndrome is a surprisingly complex and highly individualized disease, with different factors contributing toward the disease process. Many factors can induce OSA disease, such as hypertrophy uvula, adenoidectomy, tonsil caused by mechanical obstruction of the airway, airway obstruction on obesity cause of decubitus, etc.; in addition, abnormal structure and function of the central nervous system (CNS) is also one of the important factors. This paper examines the relationship of the CNS with the onset of OSA. Evidence has shown that dysfunction of the CNS may be related to the occurrence of OSA. Although modification of the behaviors of the motor neurons may offer a potentially interesting means of controlling the airway, human afferent and motor pathways that regulate eupnea are still poorly understood. Combining some clinical phenomena of patients with cerebral hemorrhage or brain trauma at the temporal lobe, it seems that no close relation with OSA has been observed in clinical work and animal experiments; however, CNS damage at the temporal lobe is involved in the pathogenesis of OSA. This article examines the role of the CNS in the pathogenesis of OSA and its mechanisms. We have summarized previous findings of OSA-related brain damage, which were obtained by brain functional MRI, clinical, and animal experiment data to better understand the roles of the CNS in the pathogenesis of OSA. More specifically, this review summarizes how altered activity of the limbic system and its related structures could be associated with the occurrence of OSA. This conclusion may contribute toward our understanding of nosogenesis and the treatment of OSA.

Incidence and clinical features of hyperlipidemic acute pancreatitis from Guangdong, China: a retrospective multicenter study.

OBJECTIVE: This study aimed to investigate the clinical features and incidence trends of hyperlipidemic acute pancreatitis (HLAP) of multicenter studies in Guangdong, China, for 15 years. METHODS: The medical records of 1582 patients with acute pancreatitis who were admitted to 4 general hospitals of Guangdong from January 1990 to December 2005 were reviewed. The inpatient medical and radiologic records were reviewed to determine clinical features, severity, complications, mortality, and recurrence rate. RESULTS: A total of 7.8% (123/1582) patients met the HLAP criteria. Incidence of HLAP was approximately 2.6 times increased during 15 years (3.4% in 1990-1994, 5.9% in 1995-1999, and 8.9% in 2000-2005, respectively) and ranged from 3.3% to 15.5% in 4 hospitals across Guangdong. A history of diabetes was present in 31.7% and alcohol use in 18.7%. The mean (SD) triglyceride levels were 13.6 (7.2) mmol/L. Amylase was elevated higher than normal in 81.2% but only 2 times normal in 17.1% and 3 times normal in 37.6%. The frequency of severe acute pancreatitis, organ dysfunction, rate of recurrence, and mortality of HLAP was significantly higher than biliary-induced pancreatitis. CONCLUSIONS: The incidence of HLAP had significantly increased during the past 15 years with a clear geographic variation and remarkable severity and recurrent trend.

[Changes of rice yield and quality in different accumulated temperature zones in Heilongjiang Province of Northeast China].

Field experiments were installed in different accumulated temperature zones in Heilongjiang Province to study the changes of the grain yield and quality of five major rice varieties with accumulated temperature. The rice yield changed with accumulated temperature in quadratic curve, and the correlation degree differed with the varieties. The panicle number and the grain number per panicle changed significantly in quadratic curve with accumulated temperature, while the 1000-grain mass had less correlation with accumulated temperature. The sterile spikelet rate of grain increased obviously from suitable accumulated temperature zone to low accumulated temperature zone, but had no obvious change from suitable accumulated temperature zone to high accumulated temperature zone. The rates of chalky and head milled rice also changed with accumulated temperature in quadratic curve, i. e., there were both the lowest and the highest values in suitable accumulated temperature zone. The protein and amylose contents of the grain as well as the taste varied little with accumulated temperature. According to the sensitivity to temperature, the test rice varieties were divided into sensitive, medium, and blunt types, with the optimal and allowable cultivation accumulated temperature limits being 300 degrees C and 420 degrees C, 360 degrees C and 440 degrees C, and 380 degrees C and 520 degrees C, respectively. It would be very important to select the rice varieties with higher yield and better quality according to the local conditions, especially the accumulated temperature.

The lateral habenula is a common target of cocaine and dexamethasone.

The lateral habenular nucleus (LHb) receives projections from areas rich in dopaminergic neurons and sends efferent fibers to these areas, suggesting that the LHb has a role in dopaminergic reward-related activity. The LHb is also implicated in multiple stress reactions, including responses to painful stimuli. However, it is unclear whether the LHb facilitates glucocorticoid/cocaine interactions by serving as a common target of both. In this study we investigated the effect of cocaine and dexamethasone (a synthesized glucocorticoid) on pain-related neurons (pain-excitatory and pain-inhibitory). Cocaine treatment effectively increased the firing rate of 89.7% of pain-excitatory neurons (cocaine-up response) and decreased the firing rate of 81.8% of pain-inhibitory neurons (cocaine-down response) in the LHb, suggesting that LHb neurons respond to cocaine via different mechanisms. Dexamethasone enhanced the firing rate of the cocaine-up neurons, while cocaine-down neurons were not influenced, indicating that both drugs may elicit an electrophysiological response at the same LHb neuron. Effects of either cocaine or dexamethasone alone, or both combined, on FOS expression in the LHb were observed via immunohistochemistry. Single administration of either cocaine or dexamethasone increased the number of FOS-positive neurons in the LHb. Pretreatment with dexamethasone and then cocaine markedly enhanced the number of FOS-positive neurons in the LHb relative to cocaine treatment alone, suggesting that stress and addictive drugs exert a synergistic effect on the LHb. We conclude that the LHb responds to cocaine via more than one mechanism and is a common target of both cocaine and the dexamethasone.

Effect of ethyl pyruvate on renal high mobility group box-1 protein expression and acute kidney injury in rats with delayed resuscitation after thermal injury / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the effect of ethyl pyruvate (EP) on high mobility group box-1 protein (HMGB1) expression in renal tissue and acute kidney injury in rats with delayed resuscitation after thermal injury.</p><p><b>METHODS</b>Seventy-eight Wistar rats subjected to 30% total body surface area full-thickness thermal injury followed with delayed resuscitation were divided into 3 groups: sham group (n = 18), injury group (n = 30) and EP group (n = 30). Renal tissue and blood samples were harvested to determine HMGB1 mRNA as well as its protein expression and renal function parameter at the 8, 24, 72 h post the "injury". HMGB1 mRNA was semi-quantitatively measured by reverse transcription polymerase chain reaction taking GAPDH as an internal standard, and HMGB1 protein expression was determined by Western blot and immunohistochemistry. Blood urea nitrogen (BUN) levels were measured with automatic biochemistry analyzer. The pathological changes of renal tissues were examined using HE staining.</p><p><b>RESULTS</b>Compared with sham controls, both mRNA and protein expressions of HMGB1 in injury group were significantly enhanced in kidneys at 8 - 72 h after thermal injury (P < 0.05), meanwhile serum BUN levels were markedly increased (P < 0.05). Compared with injury group, the renal HMGB1 mRNA and protein expressions were markedly down-regulated in EP group at 8 h, 24 h and 72 h post injury (P < 0.05), respectively, and meanwhile serum BUN levels were reduced significantly (P < 0.05). Inflammatory cell infiltration was found in renal tissues following injury, and kidney injury was markedly alleviated after treatment with EP.</p><p><b>CONCLUSIONS</b>It indicated that HMGB1 appears to be involved in the pathogenesis of post-burn acute kidney injury. Treatment with EP reduces renal HMGB1 expression, and protects against acute kidney injury secondary to delayed resuscitation after major burns.</p>

Effect of Xuebijing injection on renal high mobility group box-1 protein expression and acute kidney injury in rats after scald injury / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the change in renal high mobility group box-1 protein (HMGB1) levels, and the effect of Chinese traditional medicine-Xuebijing injection on HMGB1 expression as well as acute kidney injury in rats after scald injury.</p><p><b>METHODS</b>Wistar rats were subjected to 30% full-thickness scald injury followed with delayed resuscitation. Totally 78 animals were divided into sham scald group (n=18), scald injury group (n=30), and Xuebijing injection treatment group (n=30). All animals were sacrificed at 8, 24, and 72 hours postburn. Renal tissue and blood samples were harvested to determine HMGB1 mRNA as well as protein expression and organ functional parameters. HMGB1 mRNA level was semi-quantitatively measured by the reverse transcription polymerase chain reaction taking GAPDH as an internal standard, and protein expressions of HMGB1 were detected by both Western blot and immunohistochemistry. Serum creatinine (Cr) contents were measured by automatic biochemistry analyzer. In addition, pathological lesions in kidney were observed under light microscope using HE staining.</p><p><b>RESULTS</b>Compared with sham scald group, both mRNA and protein expressions of HMGB1 were significantly enhanced in the kidney at 8, 24, and 72 hours after scald injury (P<0.05, P<0.01), meanwhile serum Cr contents were markedly increased following acute insults (P<0.05, P<0.01). Treatment with Xuebijing injection could markedly down-regulated renal HMGB1 mRNA expression and protein release at 24 hours and 72 hours (P<0.05, P<0.01), and significantly reduced serum Cr content following scald injury (P<0.05). Many inflammatory cells in renal tissues were observed using light microscope following scald. The histological morphology of kidney lesions was a-HMGB1, a late mediator, appears to be inmeliorated after treatment with Xuebijing injection.</p><p><b>CONCLUSIONS</b>volved in the pathogenesis of excessive inflammatory response and acute kidney damage. Treatment with Xuebijing injection can inhibit HMGB1 synthesis and release in renal tissues, and may prevent the development of acute kidney injury induced by serious scald injury.</p>