沙利度胺与难治性克罗恩病的治疗进展

随着克罗恩病的治疗研究不断发展,新出现的治疗方案已经越来越针对克罗恩病的发病机理。近年来病例报道和临床试验都证明沙利度胺正在作为一种有效的可供选择的药物用以治疗难治性克罗恩病。除了可以部分下调促炎症介质肿瘤坏死因子α(TNF-α),抑制由血管内皮生长因子(VEGF)和碱性纤维母细胞生长因子(bFGF)诱导的血管增生,沙利度胺还具有其他免疫调节特性。临床研究证实,难治性克罗恩病的患者对沙利度胺的治疗有所反应。此文就沙利度胺的药理机制、作用方式、不良反应等作一综述。     

沙利度胺对人脐静脉内皮细胞增殖和血管生成的影响

目的 探讨沙利度胺治疗血管发育不良所致消化道出血的机制.方法 体外培养人脐静脉内皮细胞至对数生长期,分为空白对照组、溶剂对照组(二甲基亚砜)和不同浓度(10、20、40、60、80、100μg/ml)沙利度胺组,根据加或不加成纤维细胞生长因子(bFGF,10 ng/ml),共分为16组.刺激72 h后,MTT法检测细胞增殖情况,酶联免疫吸附法和实时定量PCR法测定血管内皮生长因子(VEGF)、肿瘤坏死因子-α(TNF-α)表达.结果 加或不加bFGF刺激,中、高浓度(≥40/μg/ml)沙利度胺均能抑制人脐静脉内皮细胞增殖.未加bFGF刺激时.20μg/ml沙利度胺能明显抑制VEGF表达.加bFGF刺激时,10 μg/ml沙利度胺即能明显抑制VEGF表达.未检出TNF-α表达.结论 体外实验中,沙利度胺能抑制人脐静脉内皮细胞增殖和VEGF表达,从而抑制血管生成,达到治疗血管发育不良所致消化道出血的目的 .     

Dll4/Notch1在消化道血管发育不良出血患者中的表达以及沙利度胺的干预机制

背景:Dll4/Notch1信号通路是肿瘤血管形成、血管发育等领域的研究热点,然而其在消化道血管发育不良(AGD)中的作用机制尚未阐明。沙利度胺常用于治疗AGD所致的消化道出血。目的:探讨Dll4/Notch1信号通路在消化道AGD形成中的作用以及沙利度胺的干预机制。方法:收集不明原因反复消化道出血、经胶囊内镜和(或)小肠镜检查确诊为AGD的患者25例和因AGD致消化道出血接受沙利度胺(100 mg/d,疗程4个月)治疗者10例,1 8名健康志愿者作为正常对照。以ELISA法检测血清Dll4、Notch1浓度。结果:AGD组血清Dll4、Notch1浓度显著高于正常对照组(P0.01),且Dll4与Notch1间呈正相关(r=0.900,P0.01)。沙利度胺治疗前后,AGD患者的血清Dll4、Notch1浓度无明显改变;根据性别和疗效进行分层分析,差异亦无统计学意义。结论:Dll4/Notch1信号通路可能参与了消化道AGD的形成,沙利度胺对该信号通路的调节作用不明显。     

沙利度胺治疗克罗恩病的研究进展

克罗恩病（CD）是一种慢性非特异性肠道炎症性疾病,其发病机制尚未完全明确。近年来随着对肿瘤坏死因子（TNF）-α在CD发病机制中的认识,针对TNF—α的靶向治疗成为关注热点。沙利度胺因具有抑制TNF-α的特性,在CD尤其是难治性CD的治疗中起一定作用。本文就沙利度胺治疗CD的研究进展作一综述。     

DII4／Notch1在消化道血管发育不良出血患者中的表达以及沙利度胺的干预机制

DII4／Notch1信号通路是肿瘤血管形成、血管发育等领域的研究热点．然而其在消化道血管发育不良（AGD）中的作用机制尚未阐明。沙利度胺常用于治疗AGD所致的消化道出血。目的：探讨DII4／Notch1信号通路在消化道AGD形成中的作用以及沙利度胺的干预机制。方法：收集不明原因反复消化道出血、经胶囊内镜和（或）小肠镜检查确诊为AGD的患者25例和因AGD致消化道出血接受沙利度胺（100mg／d．疗程4个月）治疗者10例,18名健康志愿者作为正常对照。以ELISA法检测血清DII4、Notchl浓度。结果：AGD组血清DII4、Notch1浓度显著高于正常对照组（P〈0．01）,且DII4与Notch1间呈正相关（r=0．900,P〈0．01）。沙利度胺治疗前后,AGD患者的血清DII4、Notch1浓度无明显改变;根据性别和疗效进行分层分析,差异亦无统计学意义。结论：DII4／Notch1信号通路可能参与了消化道AGD的形成．沙利度胺对该信号通路的调节作用不明显．     

沙利度胺治疗裸鼠胰腺癌皮下移植瘤的疗效观察

胰腺癌目前高居癌症死因的第4位[1],诊断后中位生存期不到6个月,1年存活率约为12％,5年存活率＜5％[2].胰腺癌确诊时多属晚期,已失去手术机会,因此,针对胰腺癌的药物研究是目前的热点之一.沙利度胺(thalidomide,THD)又名反应停,是谷氨酸的衍生物,具有抗实体肿瘤作用.体外实验研究证实[3],沙利度胺可以抑制胰腺癌SW1990细胞的增殖,促进其凋亡.本研究采用腹腔内注射沙利度胺的方法治疗人胰腺癌SW1990细胞的裸鼠移植瘤,观察其对肿瘤生长及其对血管形成的作用,探讨其机制.     

沙利度胺预防和治疗三硝基苯磺酸诱导结肠炎的研究

克罗恩病病因不明，但有研究表明肿瘤坏死因子-α（TNF-α）在该病发病机制中占有重要地位，而沙利度胺通过加速TNF-α mRNA降解而抑制TNF-α生成。我们将沙利度胺用于预防和治疗近似克罗恩病的三硝基苯磺酸（TNBS）诱导的结肠炎，以明确其效果与机制。     

缺氧条件下人脐静脉内皮细胞Ang-2、Notch1、Dll4、HIF-1α表达以及沙利度胺对其表达的影响水

背景：沙利度胺治疗胃肠道血管畸形所致的难治性消化道出血安全、有效,而胃肠道血管畸形所致的消化道出血可能与缺氧引起的血管代偿性增生有关。目的：探讨人脐静脉内皮细胞（HUVEC）血管生成素2（Ang-2）、Noteh1、Dll4和缺氧诱导因子（HIF）-1α在缺氧环境中的表达以及沙利度胺的干预机制。方法：HUVEC分别于常氧和缺氧环境下培养。缺氧培养的HUVEC分为溶剂对照组和不同浓度（25、50、100、200μg／mL）沙利度胺组。以Real-time PCR和蛋白质印迹法分别检测Ang-2、Noteh1、Dll4、HIF-1α mRNA和蛋白表达。结果：缺氧条件下Ang-2、Noteh1、Dll4、HIF-1α mRNA和蛋白表达均高于常氧状态,差异有统计学意义（P〈0．05）。沙利度胺可呈浓度依赖性地抑制HUVEC Ang-2、Noteh1、Dll4 mRNA和蛋白表达（P〈0．05）。结论：沙利度胺对Ang-2、Noteh1、Dll4表达的抑制作用可能是其抑制血管生成从而治疗胃肠道血管畸形致消化道出血的机制之一。     

沙利度胺对大鼠佐剂性关节炎的治疗作用及其对炎性细胞因子的影响

目的评价沙利度胺在佐剂性关节炎(AA)大鼠模型中的治疗作用,并探讨其可能的机制。方法随机分为模型对照组、100mg·kg-·1d-1沙利度胺治疗组、200mg·kg-·1d-1沙利度胺治疗组和正常对照组。治疗过程中连续对大鼠的关节炎症程度进行评分。治疗前后对大鼠的右后足进行放射学评分。治疗14d后,检测各组大鼠右膝关节滑膜的组织病理学改变及血清肿瘤坏死因子(TNF)-α和白细胞介素(IL)-1β的水平。结果不同剂量沙利度胺治疗组的关节炎指数、放射学及滑膜组织病理学改变均较模型对照组明显改善(P<0.05),不同剂量沙利度胺治疗组间差异无统计学意义(P>0.05);沙利度胺能显著下调AA大鼠血清TNF-α和IL-1β的水平(P<0.01和0.05),且不同剂量下TNF-α的水平差异有统计学意义(P<0.01),而IL-1β差异无统计学意义(P>0.05)。结论沙利度胺能改善AA大鼠关节炎症状、放射学及滑膜组织病理变化,并能明显降低AA大鼠血清中TNF-α和IL-1β的水平。     

沙利度胺的药理特点及其在溃疡性结肠炎中的作用

沙利度胺被认为具有免疫调节和抗血管生成作用,已被用于治疗多种免疫性疾病和血管增生性疾病。肠道黏膜免疫反应异常和血管生成异常在溃疡性结肠炎(UC)的发病机制中起重要作用。因此,沙利度胺对UC可能具有有益的治疗作用。此文结合近年来的文献资料对沙利度胺的药理特点及其在UC中的作用作一综述。     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.