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1.
Reconstitution of the functional receptors for murine and human interleukin 5 总被引:12,自引:1,他引:12
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《The Journal of experimental medicine》1993,177(6):1523-1529
The murine interleukin 5 receptor (mIL-5R) is composed of two distinct subunits, alpha and beta. The alpha subunit (mIL-5R alpha) specifically binds IL-5 with low affinity. The beta subunit (mIL-5R beta) does not bind IL-5 by itself, but forms the high-affinity receptor with mIL-5R alpha. mIL-5R beta has been revealed to be the mIL-3R-like protein, AIC2B which is shared with receptors for IL-3 and granulocyte/macrophage colony-stimulating factor. We demonstrated here the reconstitution of the functional receptors for murine and human IL- 5 on the mouse IL-2-dependent cell line, CTLL-2. CTLL-2 was transfected with the cDNAs for mIL-5R alpha and/or AIC2B. Only CTLL-2 transfectant expressing both mIL-5R alpha and AIC2B expressed the high-affinity receptor and proliferated in response to murine IL-5. Then CTLL-2 was transfected with the cDNAs for hIL-5R alpha and/or KH97 (beta c), the human homologue of AIC2B. Though beta c did not contribute much to binding affinity of hIL-5R, only CTLL-2 transfectant expressing both hIL-5R alpha and beta c proliferated in response to human IL-5. These results showed that the beta subunit is indispensable in IL-5 signal transduction. We further investigated the function of IL-5-specific alpha subunit in transmitting IL-5 signals. Mutant mIL-5R alpha, which lacks its whole cytoplasmic domain, was transfected into mouse IL-3- dependent cell line, FDC-P1 expressing AIC2B intrinsically. The resulting transfectant did not respond to IL-5, though the transfectant expressed the high-affinity IL-5R, indicating that the cytoplasmic portion of the alpha subunit also has some important role in IL-5- mediated signal transduction. 相似文献
2.
GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier 总被引:2,自引:0,他引:2
gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V(max) = 709 +/- 214 nmol/min/g, K(m) = 11.0 +/- 3.56 mM, and CL(ns) = 0.019 +/- 0.003 cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta-hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity. 相似文献
3.
BACKGROUND: Overactive bladder (OAB) is a widespread problem that has a negative effect on quality of life, particularly among the elderly. Antimuscarinic agents are the only drug class with broad, accepted efficacy in the treatment of OAB. Their clinical usefulness, however, is limited by dose-dependent adverse effects. In the elderly, the most serious of these is central nervous system (CNS) dysfunction, including cognitive impairment. OBJECTIVE: This article examines currently available antimuscarinic agents for the treatment of OAB in terms of their likelihood of causing CNS dysfunction by crossing the blood-brain barrier (BBB) and blocking muscarinic type 1 (Ml) receptor sites in the brain. METHODS: Pertinent studies were selected from a comprehensive review of the OAB literature with a focus on muscarinic receptor-associated mechanisms leading to CNS adverse effects and their potential impact on elderly patients. MEDLINE was searched for articles published in the past 10 years, and additional articles were obtained from the reference lists of identified publications. Also searched were abstracts of recent meetings of the International Consultation on Incontinence, International Continence Society, American Urological Association, and European Association of Urology. RESULTS: Antimuscarinic agents control involuntary detrusor muscle contractions through cholinergic blockade at the muscarinic receptors. The prevalence of OAB is highest in the elderly, the population most likely to be taking multiple anticholinergic medications and most vulnerable to the CNS adverse effects of these agents. Nonselective antimuscarinic agents that bind to the Ml receptor are most likely to cause significant cognitive adverse effects compared with the more selective antimuscarinic agents for the treatment of OAB. CONCLUSIONS: When considering use of an antimuscarinic agent for the treatment of OAB in elderly patients, prescribers should routinely consider the agent's receptor selectivity and ability to cross the BBB. The medical history should include all current medications that may contribute to the anticholinergic burden and cognitive impairment. Patients and caregivers should be educated to recognize anticholinergic adverse effects. 相似文献
4.
Brandon J. Kim Bryan M. Hancock Andres Bermudez Natasha Del Cid Efren Reyes Nina M. van Sorge Xavier Lauth Cameron A. Smurthwaite Brett J. Hilton Aleksandr Stotland Anirban Banerjee John Buchanan Roland Wolkowicz David Traver Kelly S. Doran 《The Journal of clinical investigation》2015,125(6):2473-2483
5.
Mohd Nor Faiz Norrrahim Mas Amira Idayu Abdul Razak Noor Aisyah Ahmad Shah Herdawati Kasim Wan Yusmawati Wan Yusoff Norhana Abdul Halim Siti Aminah Mohd Nor Siti Hasnawati Jamal Keat Khim Ong Wan Md Zin Wan Yunus Victor Feizal Knight Noor Azilah Mohd Kasim 《RSC advances》2020,10(8):4465
Organophosphorus (OP) compounds are highly toxic synthetic compounds which have been used as pesticides and developed as warfare nerve agents. They represent a threat to both military and civilian populations. OP pesticides affect the nervous system and are thought to have caused at least 5 million deaths since their discovery in the 1930s. At present the treatment of OP nerve agent poisoning commonly involves the use of parenteral oximes. However, the blood brain barrier (BBB) remains a challenge in the delivery of oximes to the central nervous system (CNS). This is because almost all macromolecule drugs (including oximes) fail to pass through the BBB to reach the CNS structures. The presence of a permanent cationic charge in oximes has made these compounds inefficient in crossing the BBB. Thus, oximes are unable to reactivate acetylcholinesterase (AChE) in the CNS. Using current structural and mechanistic understanding of the BBB under both physiological and pathological conditions, it becomes possible to design delivery systems for oximes and other drugs that are able to cross the BBB effectively. This review summarises the recent strategies in the development of oximes which are capable of crossing the BBB to treat OP poisoning. Several new developments using oximes are reviewed along with their advantages and disadvantages. This review could be beneficial for future directions in the development of oxime and other drug delivery systems into the CNS.Organophosphorus (OP) compounds are highly toxic synthetic compounds which have been used as pesticides and developed as warfare nerve agents. 相似文献
6.
Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier 总被引:7,自引:0,他引:7
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Shibata M Yamada S Kumar SR Calero M Bading J Frangione B Holtzman DM Miller CA Strickland DK Ghiso J Zlokovic BV 《The Journal of clinical investigation》2000,106(12):1489-1499
Elimination of amyloid-ss peptide (Ass) from the brain is poorly understood. After intracerebral microinjections in young mice, (125)I-Ass(1-40) was rapidly removed from the brain (t(1/2) = 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Ass(1-40) at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Ass(1-40) clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and alpha(2)-macroglobulin (alpha(2)M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Ass was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Ass accumulation in brains of Alzheimer's disease (AD) patients. We conclude that the BBB removes Ass from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by alpha(2)M and/or apoE, and may be impaired in AD. 相似文献
7.
T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines 总被引:26,自引:1,他引:25
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《The Journal of experimental medicine》1996,183(6):2593-2603
Analysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame of Herpesvirus saimiri. Here we report on the cloning of human IL-17 (hIL-17), the human counterpart of murine IL-17. hIL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4+ T cells. Although devoid of direct effects on cells of hematopoietic origin, hIL-17 and the product of its viral counterpart, ORF13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte-colony- stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hIL-17, fibroblasts could sustain the proliferation of CD34+ hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hIL-17 may constitute (a) an early initiator of the T cell-dependent inflammmatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis. 相似文献
8.
Ronaldson PT Finch JD Demarco KM Quigley CE Davis TP 《The Journal of pharmacology and experimental therapeutics》2011,336(3):827-839
Pain is a dominant symptom associated with inflammatory conditions. Pharmacotherapy with opioids may be limited by poor blood-brain barrier (BBB) permeability. One approach that may improve central nervous system (CNS) delivery is to target endogenous BBB transporters such as organic anion-transporting polypeptide 1a4 (Oatp1a4). It is critical to identify and characterize biological mechanisms that enable peripheral pain/inflammation to "transmit" upstream signals and alter CNS drug transport processes. Our goal was to investigate, in vivo, BBB functional expression of Oatp1a4 in animals subjected to peripheral inflammatory pain. Inflammatory pain was induced in female Sprague-Dawley rats (200-250 g) by subcutaneous injection of 3% λ-carrageenan into the right hind paw; control animals were injected with 0.9% saline. In rat brain microvessels, Oatp1a4 expression was increased during acute pain/inflammation. Uptake of taurocholate and [d-penicillamine(2,5)]-enkephalin, two established Oatp substrates, was increased in animals subjected to peripheral pain, suggesting increased Oatp1a4-mediated transport. Inhibition of inflammatory pain with the anti-inflammatory drug diclofenac attenuated these changes in Oatp1a4 functional expression, suggesting that inflammation in the periphery can modulate BBB transporters. In addition, diclofenac prevented changes in the peripheral signaling cytokine transforming growth factor-β1 (TGF-β1) levels and brain microvascular TGF-β receptor expression induced by inflammatory pain. Pretreatment with the pharmacological TGF-β receptor inhibitor 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide (SB431542) increased Oatp1a4 functional expression in λ-carrageenan-treated animals and saline controls, suggesting that TGF-β signaling is involved in Oatp1a4 regulation at the BBB. Our findings indicate that BBB transporters (i.e., Oatp1a4) can be targeted during drug development to improve CNS delivery of highly promising therapeutics. 相似文献
9.
Glioblastoma multiform (GBM) is the most common brain tumor. The current GBM treatments comprise of radiation therapy, chemotherapy and surgery. One of the most important problems regarding the treatment of GBM is the presence of blood brain barrier (BBB) which inhibits the efficient drug delivery into central nervous system (CNS). Nanothechnology can help to deliver therapeutic drugs into CNS through crossing the BBB. There are different types of nanoparticles (Nps) which can be manipulated for clinical applications as a treatment for CNS-related disorders. In this review, we will discuss the role of Nps in the treatment of GBM. 相似文献
10.
Bin Yang Shaoyong Li Hongyan Wang Yansu Guo Dominic J Gessler Chunyan Cao Qin Su Joshua Kramer Li Zhong Seemin Seher Ahmed Hongwei Zhang Ran He Ronald C Desrosiers Robert Brown Zuoshang Xu Guangping Gao 《Molecular therapy》2014,22(7):1299-1309
Some recombinant adeno-associated viruses (rAAVs) can cross the neonatal blood–brain barrier (BBB) and efficiently transduce cells of the central nervous system (CNS). However, in the adult CNS, transduction levels by systemically delivered rAAVs are significantly reduced, limiting their potential for CNS gene therapy. Here, we characterized 12 different rAAVEGFPs in the adult mouse CNS following intravenous delivery. We show that the capability of crossing the adult BBB and achieving widespread CNS transduction is a common character of AAV serotypes tested. Of note, rAAVrh.8 is the leading vector for robust global transduction of glial and neuronal cell types in regions of clinical importance such as cortex, caudate-putamen, hippocampus, corpus callosum, and substantia nigra. It also displays reduced peripheral tissue tropism compared to other leading vectors. Additionally, we evaluated rAAVrh.10 with and without microRNA (miRNA)-regulated expressional detargeting from peripheral tissues for systemic gene delivery to the CNS in marmosets. Our results indicate that rAAVrh.8, along with rh.10 and 9, hold the best promise for developing novel therapeutic strategies to treat neurological diseases in the adult patient population. Additionally, systemically delivered rAAVrh.10 can transduce the CNS efficiently, and its transgene expression can be limited in the periphery by endogenous miRNAs in adult marmosets. 相似文献
11.
Involvement of Interleukin (IL) 8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue 总被引:13,自引:1,他引:12
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《The Journal of experimental medicine》1996,184(5):1825-1832
Expansion of mature neutrophils has been observed in mice lacking the murine interleukin (IL) 8 receptor homolog [mIL-8Rh(-/-)], and human (hu) IL-8 suppresses proliferation of primitive myeloid cells in vitro and in vivo. To evaluate involvement and relevance of murine IL-8 receptor homolog (mIL-8Rh) in negative regulation of myelopoiesis, we studied mIL-8Rh(-/-) and (+/+) mice raised in a normal or germ-free environment. Immature myeloid progenitors from mIL-8Rh(+/+) mice bred under normal or germ-free conditions were significantly suppressed in vitro by recombinant huIL-8, macrophage inflammatory protein (MIP)-1 alpha, platelet factor (PF) 4, interferon inducible protein (IP) 10, monocyte chemotactic peptide (MCP) 1, and H-ferritin. In contrast, progenitors from mIL-8Rh(-/-) mice were insensitive to inhibition by IL- 8, but not to these other chemokines and H-ferritin. Mouse MIP-2, a ligand for mIL-8Rh, suppressed progenitors from normal but not mIL-8Rh(- /-) mice. Under normal environmental conditions, enhanced numbers of myeloid progenitors were found in femur, spleen, and blood of mIL-8Rh(- /-) compared with mIL-8Rh(+/+) mice. Numbers of myeloid progenitors were greatly decreased in mIL-8Rh(-/-)and (+/+) mice in germ-free conditions, and were either not significantly enhanced in mIL-8Rh(-/-) mice compared with (+/+) mice or were only moderately so. Differences in progenitors/organ between a germ-free and normal environment were greater for the mIL-8Rh(-/-) mice. These results document selective insensitivity of myeloid progenitor cells from mIL-8Rh(-/-) mice to inhibition by huIL-8 and mouse MIP-2 and a large expansion of myeloid progenitors in these mice, the latter effect being environmentally inducible. This provides strong support for a negative myeloid regulatory role played by the mIL-8Rh in vivo, whose active ligand may be MIP-2. 相似文献
12.
Prevention of the cryptic epitope SLAYGLR within osteopontin does not influence susceptibility to Candida albicans infection
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Sato I Yamamoto N Yamazaki H Hashimoto S Hino M Sakai F Fujie A 《Antimicrobial agents and chemotherapy》2005,49(7):3053-3055
The effect of an antiosteopontin antibody (M5 Ab) reacting with the SLAYGLR sequence within osteopontin on the host susceptibility to infection was investigated in a murine model of disseminated candidiasis. The treatment with anti-tumor necrosis factor alpha antibody enhanced fungal infection, while the treatment with M5 Ab did not affect the infection. 相似文献
13.
Macrophage- and neutrophil-dominant arthritis in human IL-1 alpha transgenic mice 总被引:4,自引:0,他引:4
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Niki Y Yamada H Seki S Kikuchi T Takaishi H Toyama Y Fujikawa K Tada N 《The Journal of clinical investigation》2001,107(9):1127-1135
To study the effects of IL-1 alpha in arthritis, we generated human IL-1 alpha (hIL-1 alpha). Transgenic mice expressed hIL-1 alpha mRNA in various organs, had high serum levels of hIL-1 alpha, and developed a severe polyarthritic phenotype at 4 weeks of age. Not only bone marrow cells but also synoviocytes from knee joints produced biologically active hIL-1 alpha. Synovitis started 2 weeks after birth, and 8-week-old mice showed hyperplasia of the synovial lining layer, the formation of hyperplastic synovium (pannus) and, ultimately, destruction of cartilage. Hyperplasia of the synovial lining was due to the accumulation of macrophage-like cells expressing F4/80 molecules. hIL-1 alpha was widely distributed in macrophage- and fibroblast-like cells of the synovial lining cells, as well as synovial fluid monocytes. T and B cells were rare in the synovial fluid, and analysis of marker expression suggests that synoviocytes were directly histolytic and did not act as antigen-presenting cells. In the joints of these mice, we found elevated levels of cells of the monocyte/macrophage and granulocyte lineages and of polymorphonuclear neutrophils (PMNs), most of which expressed Gr-1, indicating that they were mature, tissue-degrading PMNS: Cultured synoviocytes and PMNs from these animals overexpress GM-CSF, suggesting that the hematopoietic changes induced by IL-1 and the consequent PMN activation and joint destruction are mediated by this cytokine. 相似文献
14.
The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood–brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug‐targeting approaches and targeted nanotechnology‐based systems, two promising strategies for BBB targeting and delivery of drugs to the brain. 相似文献
15.
Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis 总被引:4,自引:0,他引:4
Theien BE Vanderlugt CL Eagar TN Nickerson-Nutter C Nazareno R Kuchroo VK Miller SD 《The Journal of clinical investigation》2001,107(8):995-1006
Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the alpha4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti-VLA-4 to regulate proteolipid protein (PLP) 139-151-induced R-EAE when administered either before or after disease onset. Preclinical administration of anti-VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4(+) T cells in the CNS. Most significantly, anti-VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti-VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. 相似文献
16.
An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13- induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors 总被引:8,自引:4,他引:8
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《The Journal of experimental medicine》1993,178(6):2213-2218
Interleukin 4 (IL-4) and IL-13 share many biological functions. Both cytokines promote growth of activated human B cells and induce naive human surface immunoglobulin D+ (sIgD+) B cells to produce IgG4 and IgE. Here we show that a mutant form of human IL-4, in which the tyrosine residue at position 124 is replaced by aspartic acid (hIL- 4.Y124D), specifically blocks IL-4 and IL-13-induced proliferation of B cells costimulated by anti-CD40 mAbs in a dose-dependent fashion. A mouse mutant IL-4 protein (mIL-4.Y119D), which antagonizes the biological activity of mouse IL-4, was ineffective. In addition, hIL- 4.Y124D, at concentrations of up to 40 nM, did not affect IL-2-induced B cell proliferation. hIL-4.Y124D did not have detectable agonistic activity in these B cell proliferation assays. Interestingly, hIL- 4.Y124D also strongly inhibited both IL-4 or IL-13-induced IgG4 and IgE synthesis in cultures of peripheral blood mononuclear cells, or highly purified sIgD+ B cells cultured in the presence of anti-CD40 mAbs. IL-4 and IL-13-induced IgE responses were inhibited > 95% at a approximately 50- or approximately 20-fold excess of hIL-4.Y124D, respectively, despite the fact that the IL-4 mutant protein had a weak agonistic activity. This agonistic activity was 1.6 +/- 1.9% (n = 4) of the maximal IgE responses induced by saturating concentrations of IL-4. Taken together, these data indicate that there are commonalities between the IL-4 and IL-13 receptor. In addition, since hIL-4.Y124D inhibited both IL-4 and IL-13-induced IgE synthesis, it is likely that antagonistic mutant IL-4 proteins may have potential clinical use in the treatment of IgE-mediated allergic diseases. 相似文献
17.
We evaluated the safety of agents that enhance gene transfer by modulating paracellular permeability. Lactate dehydrogenase (LDH) and cytokine release were measured in polarized primary human airway epithelial (HAE) cells after lumenal application of vehicle, ethyleneglycol-bis-(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA), sodium caprate (C10), or sodium laurate (C12). Lung toxicity was assessed after tracheobronchial instillation to murine airways and the relative ability of these agents to enhance in vivo adenoviral gene transfer was evaluated. Lumenal C12 increased LDH release in vitro, but C10 and EGTA did not. Increased levels of interleukin 8 (IL-8) were secreted from EGTA-pretreated cystic fibrosis HAE cells after apical application of Pseudomonas aeruginosa (10(8) CFU/ml), whereas IL-8 secretion from C10- and C12-pretreated cells was not different from controls. In vivo toxicity studies demonstrated no effect of EGTA, C10, or C12 on weight gain, lung edema, or bronchoalveolar lavage fluid (BALF) albumin. EGTA increased BALF cell counts, neutrophils, and murine (m) macrophage inflammatory protein 2, mKC, mIL-6, and mIL-1 beta levels. C10 had no effect on BALF cell counts or LDH, but increased murine tumor necrosis factor alpha. C12 increased BALF LDH, neutrophils, and mIL-6 levels. Histopathological analysis revealed mild focal lung inflammation more frequently in the EGTA, C10, and C12 groups than in vehicle controls, with greater intensity in the C12 group relative to the other groups. C10 and C12 also increased airway responsiveness to methacholine challenge compared with control and EGTA groups. Adenoviral gene transfer to murine trachea in vivo was enhanced more efficiently by C10 than by C12 or EGTA. Thus, the different toxicities may permit the selection of agents that enhance gene transfer with minimal adverse effects. 相似文献
18.
Yamashita Y Shimada M Minagawa R Tsujita E Harimoto N Tanaka S Shirabe K Miyazaki J Maehara Y 《Molecular cancer therapeutics》2004,3(9):1177-1182
We developed a new potent nonviral gene transfer method into mouse muscles in vivo named "electrosonoporation." We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-gamma and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial. 相似文献
19.
Nonaka N Shioda S Niehoff ML Banks WA 《The Journal of pharmacology and experimental therapeutics》2003,306(3):948-953
Peptide YY3-36 (PYY) has emerged as an important signal in the gut-brain axis, with peripherally administered PYY affecting feeding and brain function. For these effects to be direct, PYY would have to cross the blood-brain barrier (BBB). Here, we determined the permeability of the BBB to PYY radioactively labeled with 131I (I-PYY). Multiple-time regression analysis showed the unidirectional influx rate (Ki) from blood-to-brain for I-PYY to be 0.49 +/- 0.19 microl/g-min, a rate similar to that previously measured for leptin. Influx was not inhibited by 1 microg/mouse of unlabeled PYY, suggesting PYY crosses the BBB by transmembrane diffusion. About 0.176% of the i.v.-injected dose of I-PYY was taken up by brain, an amount similar to that for other peptides important in gut-brain communication. Capillary depletion showed that 69% of I-PYY crossed the BBB to enter the parenchymal space of the brain, and high-performance liquid chromatography demonstrated that the radioactivity in this space represented intact I-PYY. After intracerebroventricular injection, I-PYY crossed from brain to blood by the mechanism of bulk flow. We conclude that PYY crosses in both the blood-to-brain and brain-to-blood directions by nonsaturable mechanisms. Passage across the BBB provides a mechanism by which blood-borne PYY can affect appetite and brain function. 相似文献
20.
Christian Celia Donato Cosco Donatella Paolino Massimo Fresta 《Medicinal research reviews》2011,31(5):716-756
The blood–brain barrier (BBB) limits the transport of therapeutic molecules from the blood compartment into the brain, thus greatly reducing the species of therapeutic compounds that can be efficiently accumulated in the central nervous system (CNS). Various strategies have been proposed for improving the delivery of drugs to this tissue, and numerous invasive and noninvasive methods have been proposed by different scientists in an attempt to circumvent the BBB and to increase the delivery of drug compounds into the brain. An interesting alternative, in the solution of this problem and also that of reaching a suitable target in the CNS, has recently been provided through the use of nanoparticulate colloidal devices as a noninvasive technique for brain drug delivery. These systems offer diverse advantages over invasive strategies, because (1) they are designed using biocompatible and biodegradable materials; (2) they avoid the disruption and/or modification of the BBB; and (3) they modulate the biopharmaceutical properties of the entrapped drugs. Moreover, the possibility of targeting specific brain tissue, thanks to ligands linked to the surface of the nanoparticulate colloidal devices, confers the necessary characteristics for the treatment of CNS pathologies to these drug carriers. The aim of this review is to focus on describing the main strategies in use for designing nanoparticulate colloidal devices for CNS delivery, their potentiality as noninvasive strategies in the delivery of drugs to the cerebral tissues, and their biological and clinical applications in cerebral drug delivery. © 2010 Wiley Periodicals, Inc. Med Res Rev 31:716‐756, 2011 相似文献