慢性肾功能衰竭中医辨证客观化研究进展

对近年来慢性肾功能衰竭(CRF)中医辨证客观化研究的国内外文献进行了回顾和分析,结果表明应用现代科技手段对CRF的不同证型进行客观化研究已日趋深化,许多实验室指标与中医证型之间存在着一定的相关性,多学科、多系统、全方位的探讨CRF各证型舌脉象的客观化指标,最终有可能建立一种比较完善的辨证方法乃至新的辨证体系。     

Antagonist effect of pseudohypericin at CRF1 receptors

St. John's wort (Hypericum perforatum L.) is widely used for the treatment of mild to moderately severe depression. However, the nature of its active principles and the exact mode of antidepressant action are still unknown. It has been suggested repeatedly in preclinical and clinical studies that the content of the acylphloroglucinol hyperforin decisively contributes to the antidepressant efficacy of St. John's wort extracts. Experimental studies in vivo also indicate that the naphthodianthrone hypericin may reduce the activity of the hypothalamic-pituitary-adrenal axis. Exacerbated hypothalamic-pituitary-adrenal activity has often been associated with depressive states in patients. Corticotropin-releasing factor (CRF) seems to be a major determinant in the regulation of the hypothalamic-pituitary-adrenal activity via activation of CRF(1) receptors. In the present study, we investigated the CRF(1) receptor antagonist activity of three main constituents of St. John's wort (hypericin, pseudohypericin and hyperforin) by measuring their effect on CRF-stimulated cAMP formation in recombinant Chinese hamster ovary (CHO) cells. As a selectivity test, the compounds were also tested against calcitonin in the same cells. Of the three compounds tested, only pseudohypericin selectively antagonised CRF (K(B) 0.76 microM). Hypericin and hyperforin affected both CRF and calcitonin with similar potencies and the same type of behaviour (competitive antagonism for hypericin, noncompetitive for hyperforin). It is concluded that pseudohypericin is the only real CRF(1) receptor antagonist of the three constituents tested. In addition, evidence is provided that beside hyperforin, both pseudohypericin and hypericin are implicated in the antidepressant efficacy of St. John's wort.     

Medial prefrontal cortex suppression of the hypothalamic-pituitary-adrenal axis response to a physical stressor,systemic delivery of interleukin-1beta

Previous studies have shown that the medial prefrontal cortex can suppress the hypothalamic-pituitary-adrenal axis response to stress. However, this effect appears to vary with the type of stressor. Furthermore, the absence of direct projections between the medial prefrontal cortex and corticotropin-releasing factor cells at the apex of the hypothalamic-pituitary-adrenal axis suggest that other brain regions must act as a relay when this inhibitory mechanism is activated. In the present study, we first established that electrolytic lesions involving the prelimbic and infralimbic medial prefrontal cortex increased plasma adrenocorticotropic hormone levels seen in response to a physical stressor, the systemic delivery of interleukin-1beta. However, medial prefrontal cortex lesions did not alter plasma adrenocorticotropic hormone levels seen in response to a psychological stressor, noise. To identify brain regions that might mediate the effect of medial prefrontal cortex lesions on hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1beta, we next mapped the effects of similar lesions on interleukin-1beta-induced Fos expression in regions previously shown to regulate the hypothalamic-pituitary-adrenal axis response to this stressor. It was found that medial prefrontal cortex lesions reduced the number of Fos-positive cells in the ventral aspect of the bed nucleus of the stria terminalis. However, the final experiment, which involved combining retrograde tracing with Fos immunolabelling, revealed that bed nucleus of the stria terminalis-projecting medial prefrontal cortex neurons were largely separate from medial prefrontal cortex neurons recruited by systemic interleukin-1beta, an outcome that is difficult to reconcile with a simple medial prefrontal cortex-bed nucleus of the stria terminalis-corticotropin-releasing factor cell control circuit.     

活血益肾排浊法治疗慢性肾功能衰竭38例

观察活血益肾排浊法治疗慢性肾功能衰竭(CRF)的疗效,针对现代医学研究认为肾内凝血是促使肾功能进行性减退的主要原因之一,采用中药活血为主,益肾排浊为辅治疗CRF 38例,经2个以上疗程(4个月)治疗,结果显效13例,有效15例,无效10例,总有效率72.68%,实验室指标观察以内生肌酐清除率(Ccr)改善较明显(P＜0.01),尿素氮(BUN)、肌酐(Cr)亦下降(P＜0.05).提示活血益肾排浊法既能改善肾内微循环以延缓肾单位纤维化,又能排除体内肾毒素而缓解病情.     

Altered regulation of gene and protein expression of hypothalamic-pituitary-adrenal axis components in an immature rat model of chronic stress

Chronic stress early in postnatal life influences hormonal and behavioural responses to stress persistently, but the mechanisms and molecular cascades that are involved in this process have not been clarified. To approach these issues, a chronic stress paradigm for the neonatal rat, using limited bedding material to alter the cage environment, was devised. In 9-day-old rats subjected to this chronic stress for 1 week, significant and striking changes in the expression and release patterns of key molecules that govern the neuroendocrine stress responses were observed. The presence of sustained stress was evident from enhanced activation of peripheral elements of the neuroendocrine stress response, i.e. increased basal plasma corticosterone concentrations, high adrenal weight and decreased body weight. Central regulatory elements of the neuroendocrine stress response were perturbed, including reduced expression of hypothalamic corticotropin-releasing hormone that, surprisingly, was accompanied by reduced glucocorticoid receptor expression. Thus, the effects of chronic sustained stress in the neonatal rat on the hypothalamic-pituitary-adrenal axis included substantial changes in the expression and activity of major regulators of this axis. Importantly, the changes induced by this chronic stress differed substantially from those related to acute or recurrent stress, providing a novel model for studying the long-term effects of chronic, early life stress on neuroendocrine functions throughout life.     

Expression of corticotropin releasing factor (CRF), urocortin and CRF type 1 receptors in hypothalamic-hypophyseal systems under osmotic stimulation

The expression of corticotropin releasing factor (CRF) and urocortin in hypothalamic magnocellular neurones increases in response to osmotic challenge. To gain a better understanding of the physiological roles of CRF and urocortin in fluid homeostasis, CRF, urocortin and CRF type 1 receptor (CRFR-1) gene expression was examined in the hypothalamic-hypophyseal system usingin situ and double-label in situ hybridization following chronic salt loading. CRFR-1 expression was further examined by immunohistochemistry and receptor binding. Ingestion of hypertonic saline by Sprague-Dawley rats for 7 days induced CRF mRNA exclusively in the oxytocin neurones of the magnocellular paraventricular nucleus (PVN) and the supraoptic nucleus (SON), but induced CRFR-1 mRNA in both oxytocin and vasopressin-containing magnocellular neurones. Hypertonic saline treatment also increased urocortin mRNA expression in the PVN and the SON. In the SON, urocortin was localized to vasopressin and oxytocin neurones but was rarely seen in CRF-positive cells. Changes in CRFR-1 mRNA expression in magnocellular neurones by hypertonic saline treatment were accompanied by changes in CRFR-1 protein levels and receptor binding. Hypertonic saline treatment increased CRFR-1-like immunoreactivity in the magnocellular PVN and SON, and decreased it in the parvocellular PVN. CRF receptor binding in the PVN and SON was also increased in response to osmotic stimulation. Finally, hypertonic saline treatment increased CRFR-1 mRNA, CRFR-1-like immunoreactivity and CRF receptor binding in the intermediate pituitary. These results demonstrate that the increase in the expression of CRF and urocortin message in magnocellular neurones induced by salt loading is accompanied by an increase in CRF receptor levels and binding in the hypothalamus and intermediate pituitary. Thus, CRF and urocortin may exert modulatory effects locally within magnocellular neurones as well as at the pituitary gland in response to osmotic stimulation.     

Central orexin-A activates hypothalamic-pituitary-adrenal axis and stimulates hypothalamic corticotropin releasing factor and arginine vasopressin neurones in conscious rats

The effects of centrally injected orexin-A on plasma adrenocorticotropin (ACTH) and corticosterone levels and corticotropin releasing factor (CRF) and arginine vasopressin (AVP) mRNA in the parvocellular cells of the paraventricular nucleus (PVN) of the rat were investigated. In animals implanted previously with a lateral brain ventricle and femoral artery cannula, a single i.c.v. injection of orexin-A (10 microg/rat) resulted in a rapid, significant increase in plasma ACTH and corticosterone concentrations. Plasma ACTH reached a peak (12.5-fold greater than basal levels) at 30 min, which was maintained over 120 min before declining towards control levels by 240 min. Plasma corticosterone concentrations reached a peak (6.7-fold greater than basal levels) at 30 min. Orexin-A at a higher dose (30 microg/rat) also produced a rapid increase in plasma ACTH and corticosterone concentrations. The area under the curve for plasma levels of ACTH was similar for both doses of orexin-A. In a second study, orexin-A (10 microg/rat) was injected i.c.v. and brains and pituitaries were rapidly removed after 240 min. In situ hybridization histochemistry revealed that CRF and AVP mRNA levels were significantly increased in the parvocellular cells of the PVN. Pro-opiomelanocortin mRNA levels in the pituitary gland were not significantly elevated in response to orexin-A. These results suggest that orexin-A is able to act centrally to activate the hypothalamic-pituitary-adrenal axis involving stimulation of both CRF and AVP expression.     

前列腺素E1治疗慢性肾功能衰竭的系统评价

目的系统评价前列腺素E1治疗慢性肾功能衰竭的疗效和安全性，为临床选用前列腺素E1治疗该病提供循证药学证据。方法运用系统评价方法，全面检索PubMed（1966—2006年），CNKI（1996—2006年）等数据库，按Cochrane标准，对纳入的研究进行质量评价，采用RevMan4．2软件进行Meta分析。结果共有23个研究（1547例）符合纳入标准。Meta分析结果显示：（1）与单用常规治疗相比，在常规治疗基础上加用前列腺素E1对提高治疗总有效率和改善肾功能效果更优。包括总体有效率[OR5．36，95％CI（2．11，13．61），P=0．0004]；血尿素氮[WMD-4．50，95％CI（-5．93，-3．07），P〈0．00001]；血肌酐[WMD-74．04，95％CI（-93．97，-54．10），P〈0．00001]；内生肌酐清除率[WMD9．75，95％CI（4．45，13．05），P〈0．0001]；血红蛋白[WMD2．39，95％CI（0．58，4．19），P=0．01]；尿蛋白[WMD-0．62，95％CI（-0．95，-0．30），P=0．0002]；但对改善尿量的效果两组间差异无统计学意义[WMD90．95，95％CI（-123．50，305．41），P=0．41]。（2）前列腺素E1和黄芪相比，在降低尿素氮、降低血肌酐、提高内生肌酐清除率、降低尿蛋白效果方面均显示两组间差异无统计学意义（P〈0．05）。（3）在治疗过程中可出现轻微的血管疼痛和静脉炎，无需特殊处理可自行缓解。结论现有证据表明，在常规治疗的基础上联合前列腺素E1可有效改善慢性肾功能衰竭患者的肾功能且副作用小。     

中药对慢性肾衰竭患者血清纤维化指标的作用

目的研究中药复方肾衰泄浊汤对CRF患者血清纤维化指标的作用。方法观察肾衰泄浊汤对慢性肾衰竭患者的肾功能指标和纤维化指标的影响。结果与服用爱西特患者比较,肾衰泄浊汤有明显降低慢性肾衰竭患者血清SCr、BUN、HA、LN、PCⅢ、C-Ⅳ,明显提高CCr的作用,两者有统计学意义(P<0.01)。结论该方可抑制慢性肾衰竭患者ECM成分积聚,减轻肾组织纤维化,从而改善肾功能,延缓慢性肾衰竭进展。     

Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1

Corticotropin-releasing factor (CRF) has been hypothesized to be involved in the pathophysiology of anxiety, depression, cognitive and feeding disorders. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the CNS. However, the role for each receptor subtype in animal models of neuropsychiatric disorders remains to be determined. Using CRFR1 deficient mice, the present study investigated the functional significance of this CRF receptor subtype in anxiety-like and memory processes. CRFR1 knockout mice displayed an increased exploratory behavior in both the Elevated Plus-maze (EPM) and the Black and White (B–W) test box models of anxiety, indicating an anxiolytic-like effect of the CRFR1 gene deletion. In contrast, during the retrieval trial of a two-trial spatial memory task wild type mice made more visits to and spent more time in the novel arm as opposed to the two familiar ones of a Y-maze apparatus. No increase in the level of exploration of the novel arm by the CRFR1 deficient mice was observed. This indicates that CRFR1 knockout mice are impaired in spatial recognition memory. These results demonstrate that genetic deletion of the CRFR1 receptor can lead to impairments in anxiety-like and cognitive behaviors, supporting a critical role for this receptor in anxiety and cognitive biological processes.