We have demonstrated that analogues of alpha-mannosyl ceramide (alpha-ManCer) consisting of a series of immunosuppressive 2-aminoalcohol derivatives in place of sphingosine promote a greater immune response from mouse invariant Valpha19-Jalpha26 (AV19-AJ33) TCR-bearing NKT (Valpha19 NKT) cells than alpha-ManCer itself. To further characterize the immune responses of Valpha19 NKT cells to the alpha-ManCer analogues, cytokine production by the cells was examined in detail. We found that certain alpha-ManCer derivatives individually induced either Th1- or Th2-dominant cytokine production in culture. The Th1- or Th2-biased immune responses of Valpha19 NKT cells were dependent on MHC class I-like MR1, since they were induced by coculture with the MR1 transfectants previously loaded with the glycolipids and were inhibited in the presence of anti-MR1 antiserum. Presumably, the recognition of the alpha-mannosyl residue of the alpha-ManCer analogues by the invariant TCR is individually modulated, depending on the altered interaction with the groove of the antigen-presenting MR1. Priming of the Valpha19 invariant TCR-transgenic mice in vivo with these glycolipid derivatives resulted in the induction of the Th1- or Th2-biased immune responses. Thus, these alpha-ManCer derivatives are likely to be useful in immunotherapy for either Th1 or Th2 excess autoimmune diseases, modulating the function of Valpha19 NKT cells. 相似文献
Dynamic changes of deficits in canal and otolith vestibulo-ocular reflexes (VORs) to high acceleration, eccentric yaw rotations
were investigated in five subjects aged 25–65 years before and at frequent intervals 3–451 days following unilateral vestibular
deafferentation (UVD) due to labyrinthectomy or vestibular neurectomy. Eye and head movements were recorded using magnetic
search coils during transients of directionally random, whole-body rotation in darkness at peak acceleration 2,800°/s2. Canal VORs were characterized during rotation about a mid-otolith axis, viewing a target 500 cm distant until rotation onset
in darkness. Otolith VOR responses were characterized by the increase in VOR gain during identical rotation about an axis
13 cm posterior to the otoliths, initially viewing a target 15 cm distant. Pre-UVD canal gain was directionally symmetrical,
averaging 0.87 ± 0.02 (±SEM). Contralesional canal gain declined from pre-UVD by an average of 22% in the first 3–5 days post-UVD,
before recovering to an asymptote of close 90% of pre-UVD level at 1–3 months. This recovery corresponded to resolution of
spontaneous nystagmus. Ipsilesional gain declined to 59%, and showed no consistent recovery afterwards. Pre-UVD otolith gain
was directionally symmetrical, averaging 0.56 ± 0.02. Immediately after UVD, the contralesional otolith gain declined to 0.30 ± 0.02,
and did not recover. Ipsilesional otolith gain declined profoundly to 0.08 ± 0.03 (P < 0.01), and never recovered. In contrast to the modest and directionally symmetrical effect of UVD on the human otolith
VOR during pure translational acceleration, otolith gain during eccentric yaw rotation exhibited a profound and lasting deficit
that might be diagnostically useful in lateralizing otolith pathology. Most recovery of the human canal gain to high acceleration
transients following UVD is for contralesional head rotation, occurring within 3 months as spontaneous nystagmus resolves.
Grant support: United States Public Health Service grants DC-02952 and AG-09693. JLD is Leonard Apt Professor of Ophthalmology. 相似文献
Breast cancer resistance protein (BCRP) transporter is an efflux transporter that utilizes energy from adenosine triphosphate hydrolysis to push its substrates, regardless of the concentration gradient. Its presence on the apical membrane of the intestinal mucosa is a major obstacle for the intestinal absorption of its substrates. In this study, we examined the effects of various pharmaceutical excipients on the intestinal transport and absorption of sulfasalazine, a BCRP substrate. Four excipients, including 0.05% and 0.075% BL-9EX, 0.01% and 0.05% Brij 97, 0.075% Labrasol, and 0.05% and 0.1% Tween 20 decreased the secretory transport of sulfasalazine in an in vitro diffusion chamber. Further investigation in an in situ closed loop experiment in rats showed that 0.05% and 0.1% BL-9EX and 0.1% Brij 97 effectively enhanced the intestinal absorption of sulfasalazine while maintaining minimal toxicity to the intestinal mucosa. However, 0.1% Brij 97 also increased the intestinal absorption of 5(6)-carboxyfluorescein, a paracellular marker compound. These findings suggest that BL-9EX might effectively inhibit the BCRP-mediated efflux of sulfasalazine in vivo, indicating that BL-9EX could improve the intestinal absorption of sulfasalazine and other BCRP substrates. 相似文献
Lignans are widely distributed in plants and exhibit significant pharmacological effects, including anti-tumor and antioxidative activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca asoca by monitoring antioxidative activity using the 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Starting from a tandem Michael-aldol reaction, the lignan skeleton was synthesized in 6 steps, including a cyclization step. To determine the stereochemistry of 1, we synthesized the natural product (±)-isolariciresinol (18) from alcohol 17. Comparison of the spectral data showed good agreement. Glycosylation was investigated using four different glycosyl donors. Only the Koenigs–Knorr condition using silver trifluoromethanesulfonate with 1,1,3,3-tetramethylurea provided the glycosylated product. Deprotection and purification using reverse-phase high-performance liquid chromatography gave schizandriside (1) and its diastereomer saracoside (2). Synthesized 1, 2 and 18 showed antioxidant activity with IC50?=?34.4, 28.8, 53.0 μM, respectively. 相似文献
Journal of Natural Medicines - A new amide, named dehydropropylpantothenamide (1), was obtained by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of the mouse macrophage-like cell... 相似文献
Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56 mg/kg were intravenously infused over 10 min (n = 4 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs. 相似文献
Introduction: This article provides a global overview of patent deposits for broadly neutralizing antibodies (bNAbs), which have emerged as a key strategy for HIV cure and future HIV vaccines. Scientific and technological barriers to the discovery of an effective HIV vaccine in the last 40 years have raised concerns on the potential for relevant advances in this area. Nevertheless, recent breakthrough studies have identified novel immune pathways for new innovative HIV vaccine and HIV cure strategies.
Areas covered: In our patent study, we have identified in a global scale, in the last decade, a sharp increase in the number of bNAbs’ patent deposits related to HIV prevention and treatment strategies, reaching 90 bNAbs in 2017, protected by 184 different patent deposits. Refining our patent search to the different stages of bNAbs’ development has also allowed us to identify 12 of them already at clinical stage of research (VRC01, 10E8, 3BNC117, 10-1074, 2G12, 2F5, KD-247, 4E10, PG9, PGDM1400, PGT121, and VRC07). We describe these recent breakthroughs and discuss the prospects and limitations of these novel strategies.
Expert opinion: Our results indicate the intellectual property outcomes of a scientific revolution in this field, expressing innovative modifications in antibodies to increase their potency and half-life, which have resulted in extremely potent antibodies that could provide novel preventive and therapeutic HIV strategies. 相似文献
The overall approach to managing stable COPD should be characterized by a stepwise increase in treatment, depending on the severity of the disease in accordance with JRS COPD guideline. None of the existing medications has been shown to modify the long term decline in lung function that is the hallmark of this disease. Therefore, pharmacothepary for COPD is used to decrease symptoms and/or complications. Smoking cessation and influenza vaccines are the base of pharmacotherapy. And the principal short and long acting bronchodilator treatments are anticholinergics, beta2-agonists, methylxanthines, and a combination of one or more of these drugs. And regular treatment with inhaled glucocorticosteroids should only be prescribed for symptomatic COPD patients with a documented spirometric response to glucocorticosteroids or for those with stage III and repeated exacerbations. 相似文献