Immunosuppression and recovery of drug-impaired host resistance against Candida albicans infection by oxoglaucine.

The immunosuppressive action of aporphinoid alkaloid oxoglaucine was studied in experimental Candida albicans (C. albicans) infection in mice. The alkaloid augmented host resistance to pathogen applied to mice (6-8 weeks of age) at a low dose of 2 mg kg(-1) in 3 days and impaired it at a high dose of 10 mg kg(-1). The suppressive activity observed under the latter schedule correlated with the inhibited proliferative response of splenic cells to mitogens and with decreased popliteal lymph node (PLN) reaction to C. albicans. Treatment of mice with oxoglaucine (at the age of 5 days) at a dose of 5 mg kg(-1) in 3 consecutive days increased the susceptibility to Candida inoculation at the age of 6 weeks. Delayed type hypersensitivity (DTH) response to C. albicans was enhanced after pretreatment of adult mice and was suppressed after administration to newborn mice. Long-time treatment (10 days) with oxoglaucine, cyclophoshamide or prednisolone at a dose of 10 mg kg(-1) increased the rate of mortality of Candida-infected mice. Combined pretreatment of mice with cyclophosphamide or prednisolone (5 days at a dose of 5 mg kg(-1)) followed by oxoglaucine (5 days at a dose of 5 mg kg(-1)), prolonged the survival of infected mice.     

Role of polymorphonuclear leukocytes in the resistance of tumor-bearing mice against Candida albicans infection

Tumor-bearing mice showed a significant resistance against Candida albicans intravenous infection. Longer survival was observed in groups of mice inoculated with fungal cells 2-3 weeks after tumor transplantation with allogeneic sarcoma 180, syngeneic methylcholanthrene-induced Meth A fibrosarcoma, and MM 46 mammary carcinoma than in non-tumor-bearing mice inoculated only with fungal cells. This effect was not observed when the mice were infected only 1 week after tumor transplantation. A significant decrease in the number of C. albicans cells in the kidneys was observed in mice inoculated with fungal cells 2-3 weeks after tumor transplantation. In the tumor-bearing mice treated with cyclophosphamide (CY), a remarkable decrease in both the number of peripheral blood polymorphonuclear leukocytes (PMNs) and the defense against challenge with C. albicans cells was observed, as compared with the CY-untreated groups (normal and tumor-bearing mice). A marked increase in the calcium concentration in serum and number, candidacidal activity, active oxygen level, and myeloperoxidase activity of PMNs was observed in the 2-3-week tumor-bearing mice. From these results, it is suggested that PMNs, which accumulated in the 2-3-week tumor-bearing mice, play an important role in the protection from C. albicans infection by increasing the number and the types of killing factors.     

Enhancement of antitumor effect of cytotoxic agents by bestatin

Bestatin enhanced the antitumor effects of mitomycin C, 5-fluorouracil and cis-dichlorodiammineplatinum against a syngeneic solid tumor of colon adenocarcinoma 26 in BALB/c mice. The enhancement was dependent on administration schedule. Bestatin administration after treatment with the cytotoxic agents was more effective than that made before the treatment.     

白色念珠菌耐药性产生的分子机制

耐氟康唑的白色念珠菌已成为临床长期用药治疗的一个突出性问题,目前认为白色念珠菌耐药性产生的分子机制,主要包括麦角甾醇生物合成通路中关键靶酶的变异和高表达、多药耐药蛋白对真菌胞内药物浓度的影响以及生物被膜的形成等.     

Enhancement of interleukin 1 and interleukin 2 releases by ubenimex

The effect of ubenimex on the release of interleukin 1 (IL-1) and interleukin 2 (IL-2) from immuno-competent cells was studied. Ubenimex enhanced release of IL-1 from mouse peritoneal macrophages at 1.0 and 100 micrograms/ml in vitro and the release at 1.0 microgram/ml was larger. When ubenimex was administered to mice IL-1-releasing activity of the peritoneal macrophages was enhanced 3 and 5 days after the administration but not enhanced 1 day after the administration. Ubenimex also enhanced IL-2 release from rat spleen cells at 0.1 and 10 micrograms/ml, when concanavalin A (Con A) was added in the IL-2-releasing system. The enhancement was still observed with mouse spleen cells, when serum was further added. Moreover, thymocyte-proliferating activity was attained in the broths which rat spleen cells were incubated with ubenimex from 0.1 to 10 micrograms/ml in the absence and presence of Con A.     

大蒜素抗白色念珠菌感染的免疫学机制

目的：探讨大蒜素抗白色念珠菌感染的免疫学机制,以期为系统性白色念珠菌感染的临床治疗提供实验依据。方法：分别建立正常小鼠和免疫抑制小鼠系统性白色念珠菌感染模型,并随机分为对照组和用药组。各用药组小鼠给予大蒜素7d,对照组同期给予等量生理盐水。用MTT法、双抗体夹心ELISA法、平板菌落计数法分别检测大蒜素对各感染小鼠脾脏T淋巴细胞增殖活性、IFN-γ水平及内脏活菌数目的影响。结果：经组织病理鉴定,小鼠系统性白色念珠菌感染模型建立成功。各用药组使用大蒜素7d后,脾脏T淋巴细胞增殖活性、IFN-γ水平与各自对照组比较均显著提高,差异有统计学意义（P〈0.01）,而内脏活菌数目较之对照组有明显下降,差异亦有统计学意义（P〈0.01）。结论：大蒜素能够有效提高正常感染小鼠和免疫功能低下小鼠脾脏T淋巴细胞增殖活性、IFN-γ水平,并能降低组织中白色念珠菌活菌数目。     

Enhancement of colony formation of mouse bone marrow cells by ubenimex

Ubenimex enhanced colony formation of bone marrow cells from CDF1 mice induced by L920 cell supernatant, which shows a macrophage-colony-stimulating activity (M-CSA), and also enhanced the colony formation induced CDF1 mouse spleen cell conditioned medium, which shows a granulocyte and macrophage-colony-stimulating activity. The maximal effect was obtained at 0.01 microgram/ml. But, ubenimex showed no effect on the nature of the colonies induced by each CSA. By preincubation of the bone marrow cells with ubenimex, M-CSA-induced colony-forming and the M-CSA-binding activities of the cells were increased. These results suggest that ubenimex enhances the CSA-induced colony formation of bone marrow progenitor cells of CDF1 mouse by increasing the amount of the CSA-binding to the cells.     

Efficacy of antibacterial drugs in mice with complex infection by Candida albicans and Escherichia coli.

We investigated the effect of seven antibacterial antibiotics: kanamycin, gentamicin, tetracycline, minocycline, ampicillin, piperacillin and cefotaxime, on survival of mice infected sequentially with a lethal dose of Candida albicans and a sublethal dose of Escherichia coli. The mortality of C. albicans-infected mice was facilitated by the superinfection with E. coli. When administered to mice with C. albicans/E. coli complex infection, aminoglycosides and tetracyclines significantly prolonged the survival period as compared with the infected and untreated controls. The recovery of viable counts of E. coli from the renal tissues was rapidly reduced by the treatment with gentamicin or minocycline, compared to the untreated control. Thus it was concluded that nullification by the treatment with aminoglycosides or tetracyclines of the enhancing effect of E. coli superinfection on the lethality of C. albicans-infected mice is due to early elimination of E. coli from the kidney.     

Enhancement of non-specific resistance to viral infection by muramyldipeptide and its analogs

Antiviral activity of muramyldipeptide (MDP) and its lipophilic derivatives, B30-MDP and MDP-Lys(L18), was investigated in mice infected with vaccinia virus (VV) and herpes simplex virus type 2 (HSV-2). Mice administered these compounds subcutaneously or orally were protected against VV in tail lesion tests and against HSV-2 in skin lesion tests, respectively. Since in vitro antiviral activity was not demonstrated with these compounds in cultured mammalian cells infected with either VV or HSV-2, host-mediated defense mechanisms may play a role in the activity of the compounds. As for serum interferon (IFN) induction, MDP and its analogs showed no activity in mice, suggesting that IFN does not participate in the antiviral mechanisms against VV and HSV-2. An extrinsic antiviral activity was demonstrated when peritoneal macrophages from the mice administered these compounds were cocultivated with VV-infected 3T3 cells. The results indicate that macrophage activation by MDP and its analogs plays a role in the defense mechanisms against viral infection. This activity was not virus-specific. We also demonstrate that the introduction of lipophilic residue(s) into MDP enhances the antiviral activity of mice against VV and HSV-2.     

Fluconazole resistance in Candida albicans: a review of mechanisms

Antifungal agents have greatly contributed to the improvement of public health. Nevertheless, antifungal resistant pathogens have increased during the past decade, becoming a serious concern. Candida albicans has been the most extensively studied pathogen in antifungal resistance because of their morbidity and mortality associated with infections in immunocompromised patients. This review describes the antifungal mechanims of the azole fluconazole widely used for the prophylaxis and treatment of candidal infections. The specific molecular pathways occurring in fluconazole-resistance of C. albicans and some issues about new antifungal agents are also discussed.     

Enhancement of graft-versus-host reaction and delayed cutaneous hypersensitivity in mice by ubenimex

The effect of ubenimex on graft-versus-host reaction and delayed cutaneous hypersensitivity in mice was studied. Ubenimex enhanced the graft-versus-host reaction in a dose range from 0.005 to 0.5 mg/kg. Ubenimex inhibited the aging-caused decrease of delayed cutaneous hypersensitivity to oxazolone and the efficacy was greater with older mice. Ubenimex also inhibited mitomycin C and L1210-caused decreases of delayed cutaneous hypersensitivity to picryl chloride. However, the excess decrease caused by mitomycin C was not significantly altered by ubenimex.     

白念珠菌耐药机制的研究进展

近年来白念珠菌感染发病率剧增,随着抗真菌药物的广泛使用,耐药菌株不断出现,耐药现象已经成为药物治疗的严峻挑战。目前已经明确的耐药机制包括：膜转运蛋白的过度表达,药物作用靶酶基因过度表达或突变,甾醇合成通路中其他酶的改变,生物被膜的形成,小囊状空泡的影响等。本文对白念珠菌的耐药机制做一综述。     

深部白色念珠菌感染临床株基因分型及药敏分析

目的　了解天津地区院内深部白色念珠菌感染的好发部位 ,分析危险因素 ,研究其基因分型及不同基因型药敏分析。方法　收集深部白色念珠菌感染病例及临床分离株 ,应用 PCR方法扩增白色念珠菌2 5 S r DNA基因内含子区 ,内含子大小及其中可转座 型内含子片段的缺失或插入作为分型依据。采用微量肉汤稀释法对不同基因型白色念珠菌进行药敏分析。结果　深部白色念珠菌感染以肺部感染为主 ,老年患者居多 ,均有基础疾病 ,抗生素、激素的大量使用、各种侵入性操作及免疫功能低下是重要危险因素。临床分离的 2 5株白色念珠菌经 PCR分为三型 :A型 12株 (45 0 bp) ,B型 10株 (84 0 bp) ,C型 3株 (45 0 bp、84 0 bp)。A、B型为主要基因型 ,其药敏结果无显著性差异。结论　必须重视院内深部念珠菌感染的预防和监控。PCR方法快速简捷、特异性强、重复性好 ,比较适合临床白色念珠菌的分型研究。     

Deltamethrin exposure affects host resistance to Plasmodium infection in mice

Effects of exposure to deltamethrin on host resistance to malaria infection (Plasmodium berghei) were examined in Swiss albino male mice. Four doses of deltamethrin were initially tested with two non-lethal doses, 5 and 10mg/kg, selected for more detailed study. Survival times of infected mice did not change when they were exposed to the compound for 14 days before the infection. However, survival times were shortened when they were exposed to the compound, particularly at the high-dose, after and during the initial infection. Percent parasitemia of these animals also elevated faster than that of the control. Deltamethrin exposure also caused alteration of white blood cell populations. Specifically, total white blood cell and lymphocyte counts significantly decreased in the high-dose treated mice. Granulocyte counts were comparatively lower in both treated groups than that in the control. Red blood cells, hemoglobin, and hematocrit were not affected. The obtained results suggest that deltamethrin exhibits an immunosuppressive effect and negatively impacts host resistance to malaria infection.