The Use of Two Immunosuppressive Drugs,Cyclosporin A and Tacrolimus,to Inhibit Virus Replication and Apoptosis in Cells Infected with Feline Immunodeficiency Virus

An in vitro model of acute and chronic infections with feline immunodeficiency virus (FIV) was used to examine the effect of two immunosuppressive agents, cyclosporin A (CsA) and tacrolimus (also known as FK506), on the inhibition of the replication of the virus and of apoptosis. Both drugs significantly suppressed virus production in a dose-dependent manner in acutely and chronically infected cells. The ability of FK506 to inhibit virus replication was much lower than that of CsA, and was accompanied by marked antiproliferative activity. Treatment of infected cells with either CsA or FK506 did not affect the rise of free intracellular Ca2+ but did protect the cells against apoptosis. Thus, the antiviral activity of CsA and FK506 makes these compounds promising candidates for the development of drugs suitable for the treatment of AIDS.     

Cyclosporin A metabolism in brown bullhead, Ameriurus nebulosus

Fungi suggested to be used in the control of mosquito larvae produce biologically active cyclopeptides – cyclosporins, which can potentially accumulate in the fish feeding the infected larvae. Whereas toxicity of cyclosporins was observed at the higher doses in man and various experimental animals, the fish tolerated surprisingly high cyclosporin blood levels. Hydroxy-cyclosporins predominated among metabolites excreted into water. In contrast, various N-demethylated cyclosporins created the major part of metabolites identified in the liver and bile. Two new metabolites are described – AM1N and AM6N,10N, which were not so far reported from mammals. Due to the much higher tolerance to cyclosporin, brown bullhead can serve the experimental model to obtain cyclosporin metabolites.     

A case of fatal systemic toxoplasmosis in a cat being treated with cyclosporin A for feline atopy

Acute systemic toxoplasmosis was diagnosed in a 4-5-year-old, male, Domestic Short Hair cat, which had been on cyclosporine A immunomodulatory therapy for feline atopy, over an 8-month period. Cyclosporin A (CsA) has shown promising results as a immunosuppressive agent in the cat for the treatment of eosinophilic plaque and granulomas, allergic cervico-facial pruritus, feline atopy and other immune-mediated dermatoses. However, inhibition of T-lymphocyte function by CsA is believed to have predisposed this cat to the development of a newly acquired, acute Toxoplasma gondii infection, as characterized by severe hepatic and pancreatic pathology in conjunction with the heavy parasite load demonstrated on immunohistochemical (IHC) stains for T. gondii. Cats on CsA therapy appear to be at risk of developing fatal systemic toxoplasmosis.     

Nitric oxide accumulation and actin distribution during auxin-induced adventitious root development in sunflower

Auxin-mediated adventitious root (AR) formation from the basal ends of hypocotyl segments in sunflower (Helianthus annuus L., cv. Morden) is associated with gradual subcellular and anatomical changes. Pre-mitotic events (induction phase) are evident within 1 d (24 h) in the interfascicular parenchyma. Evidence for nitric oxide (NO) accumulation in the interfascicular cells 2 d after indole-3-acetic acid (IAA) treatment, highlights the involvement of NO specifically during root initiation, following AR induction phase. Thus, adventitious root induction and initiation can be distinguished as NO-independent and NO-dependent phases. Treatment of hypocotyl explants with 10 μM 1-napthylphthlamic acid (NPA), an inhibitor of polar auxin transport in plant cells, leads to complete abolition of NO-associated fluorescence, detected upon incubation of hypocotyl sections with 4,5-diaminofluorescein diacetate (DAF-2DA). This indicates a signaling link between auxin transport and NO accumulation in the target cells. Latrunculin B (Lat B), an actin depolymerizing agent, leads to substantial inhibition of IAA-induced AR response and NO accumulation in the responding cells. Aminoguanidine [an inhibitor of inducible form of nitric oxide synthase (iNOS)] brings about a reduction in the tissue NO content, indicating a significant activity of putative NOS leading to endogenous NO accumulation. Confocal laser scanning microscope (CLSM) imaging has revealed bundling of actin with NPA and Lat B treatments. A probable interaction is thus evident between actin and NO during auxin-mediated AR formation in the initiation and extension phase. Present work, thus, provides novel observations on an interaction among endogenous NO, IAA and actin at specific stages of AR formation.     

Effect of cyclosporin A on murine experimental Salmonellosis

Investigations were undertaken to evaluate the effect of cyclosporin A (CyA) on primary infection of mice with Salmonella typhimurium. Further, its effect on delayed-type hypersensitivity (DTH) and antibody response to porin, an outer membrane protein of S. typhimurium, has been characterized under different CyA regimen. When mice were infected i.p. with 5 × 10⁴ live medium virulent organisms, the bacterial growth increased by about 2 log₁₀ in CyA treated mice. CyA administered daily for 2 weeks following immunization with porin caused profound suppression of DTH and both IgM and IgG antibody responses. Given a single dose of CyA 24 h before DTH elicitation, the drug had a marked suppressive effect on DTH, but not on the antibody response to porin. Treatment on days 0–5 following immunization had no effect on the manifestation of the DTH response nor on the anti-porin IgM response whereas an enhanced level of IgG was observed in this group.     

环孢菌素A和苯磺酸氨氯地平对慢性缺氧致大鼠右心室肥厚的作用

目的探讨环孢菌素A（Cs A）和苯磺酸氨氯地平片（Norvasc）对大鼠慢性缺氧所致右心室肥厚的作用。方法48只SD大鼠随机分为慢性缺氧组、Cs A处理组、Norvasc处理组及正常对照组。慢性缺氧组、Cs A处理组、Norvasc处理组大鼠均置于缺氧仓内连续缺氧21 d,缺氧第1天始每天分别用生理盐水和Cs A10 mg/（kg·d）腹腔注射、Norvasc 30 mg/2＋（kg·d）灌胃,共21 d。检测右心室（RV）、左心室（LV）、室间隔（S）和体质量（BW）、Ca N和[Ca]i活性、以及Cn A、-MHC表达水平。结果慢性缺氧组RV/（LV＋S）、RV/BW比值、-MHC表达高于Cs A和Norvasc处理组、正常对照组（P〈0.01）;2＋Norvasc处理组[Ca]i、Ca N活性低于慢性缺氧组（P〈0.01）,而Cs A处理组仅有Ca N活性低于慢性缺氧组（P〈0.01）。结论2＋Cs A和Norvasc可能通过抑制[Ca]i、Ca N活性来防止慢性缺氧致大鼠右心室肥厚。