血管活性肠肽受体显像及治疗研究进展

血管活性肠肽(VIP)是由28个氨基酸组成的小分子多肽,属胰高血糖素-胰泌素家族,通过其受体( VIPR)介导,调节正常及肿瘤细胞的增殖与分化.多种类型的肿瘤细胞膜上表达高密度及高亲和力VIPR,为实现肿瘤放射性核素标记VIPR显像及靶向治疗提供了分子基础.新的VIPR放射性配体的研发极大地推动了肿瘤VIPR显像及治疗...     

Balloon Pulmonary Angioplasty for the Treatment of Nonoperable Chronic Thromboembolic Pulmonary Hypertension: Single-Center Experience with Low Initial Complication Rate

PurposeTo evaluate the safety and efficacy of balloon pulmonary angioplasty (BPA) for nonoperable chronic thromboembolic pulmonary hypertension (CTEPH) patients during the initial experience of a single center.MethodsA total of 18 CTEPH patients (5 with residual pulmonary hypertension after pulmonary endarterectomy) were treated with BPA during the period 2014–2018 and were retrospectively reviewed. Mean age was 61 ± 19 years; 55% were female; mean pulmonary artery pressure was 44 ± 12 mmHg; cardiac output was 4.3 ± 1.0 l/min; and pulmonary vascular resistance was 8.4 ± 3.6 WU. Patients were evaluated by New York Heart Association functional class, 6-minute walk distance, N-terminal pro b-type natriuretic peptide, echocardiography, right heart catheterization, and before and after completions of BPA.ResultsA total of 91 procedures were performed, with a median number of 4 BPA sessions per patient (range, 2–8). There were no deaths or major complications requiring extracorporeal support or (non)invasive ventilation. The most common complication was self-limiting hemoptysis (3%). According to Society of Interventional Radiology classification, 4 mild, 4 moderate, and 1 severe adverse events were noted. Invasive hemodynamics significantly improved, with a cardiac index increase of 15% (P = .0333), decrease of mean pulmonary artery pressure of 30% (P = .0013), and decrease of pulmonary vascular resistance of 45% (P = .0048). Stroke volume index (P = .0171) and pulmonary arterial compliance (P = .0004) were also significantly enhanced.ConclusionsBPA significantly improves cardiopulmonary hemodynamics with an acceptable safety profile. Further studies assessing the long-term efficacy of BPA are required.     

Proteomic genotyping of fingermark donors with genetically variant peptides

Proteomic genotyping detects single amino acid polymorphisms to infer the genotype of corresponding non-synonymous SNPs. Like any DNA genotype, these inferences can be used to estimate random match probability. Fingermarks are a common source of biological evidence that is sample limited and a highly variable source of identifying DNA. Genetically variant peptides from fingermarks, that contain single amino acid polymorphisms, are an additional source of identifying genetic information. To discover these peptide biomarkers epidermal corneocytes from 9 subjects were isolated, processed, digested with trypsin and applied to mass spectrometry. The resulting proteomic and matching exome datasets were used to discover, characterize and validate 60 genetically variant peptides. An average of 28.8 ± 4.4 genetically variant peptides were detected from each subject resulting in a total of 264 SNP allele inferences with 260 true and 4 false positives, a false discovery rate of 1.5%. Random match probabilities were estimated using the genotype frequencies from the matching major populations in the 1000 Genomes Project. Estimates ranged up to a value of 1 in 1.7 × 10⁸, with a median probability of 1 in 2.4 × 10⁶. Furthermore, the proteomically-inferred genotypes are likely to be compatible with the STR-based random match probability estimates since the closest STR locus was 2.2 Mb from the nearest GVP-inferred SNP. This project represents a novel mode of genetic information that can be obtained from fingermarks and has the potential to complement other methods of human identification including analysis of ridge patterns or touch DNA.     

Electrophysiological Effects of atrial Natriuretic Peptide on the Cardiac Conduction System in Man

We assessed the effect of atrial natriuretic peptide (ANP) on electrophysiological parameters in man. Electrophysiological parameters were measured before, at 15, and at 30 minutes after the commencement of ANP or placebo infusions (six patients in each group). ANP levels were normal prior to infusion and rose with ANP to 159 ± 43 pmol/L, but were stable during placebo infusion. No change in heart rate or blood pressure occurred in either group. ANP infusion resulted in significant falls in intraatrial conduction time (60 ± 15 to 49 ± 15 msec), PR interval (170 ± 21 to 155 ± 16 msec), right atrial effective refractory period (232 ± 33 to 218 ± 33 msec), and ventriculoatrial refractory period (452 ± 148 to 393 ± 183 msec) while no change was seen with placebo. We conclude that ANP infusion appears to affect atrial refractoriness and velocity of conduction and atrioventricular nodal refractoriness. However, the mechanism of action and clinical significance of this observation remain to be determined.     

Human C-peptide immunoreactivity (CPR) in blood and urine — Evaluation of a radioimmunoassay method and its clinical applications

Summary A double-antibody radioimmunoassay method, using synthetic human connecting peptide as an immunizing antigen and standard, was evaluated for clinical assay of blood and urine samples. Normal fasting blood connecting peptide immunoreacivity (CPR) was 2.45±0.96 ng/ml, increasing promptly after a 50 g oral glucose load, but somewhat slower than insulin. Molar concentration of CPR exceeded that of insulin. CPR responses to glucose were subnormal in diabetics, very low in juvenile-type cases, and often poor in patients on insulin treatment. Fasting CPR levels were elevated in patients on corticosteroid treatment and with uraemia. A patient with insulin auto-antibod had high serum CPR. A considerable amount of CPR appeared in urine. Normal daily excretion of CPR was 1.52±0.55 g/kg or 55.1±18.2 ng/mg creatinine. Urine CPR was very low in juvenile-type diabetics, and elevated in patients on corticosteroid treatment. The results confirm that blood and urine CPR are useful measures of the endocrine pancreatic function.     

Developmental programing of thirst and sodium appetite

Thirst and sodium appetite are the sensations responsible for the motivated behaviors of water and salt intake, respectively, and both are essential responses for the maintenance of hydromineral homeostasis in animals. These sensations and their related behaviors develop very early in the postnatal period in animals. Many studies have demonstrated several pre- and postnatal stimuli that are responsible for the developmental programing of thirst and sodium appetite and, consequently, the pattern of water and salt intake in adulthood in need-free or need-induced conditions. The literature systematically reports the involvement of dietary changes, hydromineral and cardiovascular challenges, renin–angiotensin system and steroid hormone disturbances, and lifestyle in these developmental factors. Therefore, this review will address how pre- and postnatal challenges can program lifelong thirst and sodium appetite in animals and humans, as well as which neuroendocrine substrates are involved. In addition, the possible epigenetic molecular mechanisms responsible for the developmental programing of drinking behavior, the clinical implications of hydromineral disturbances during pre- and postnatal periods, and the developmental origins of adult hydromineral behavior will be discussed.     

Vasoactive intestinal peptide is a local mediator in a gut‐brain neural axis activating intestinal gluconeogenesis

Intestinal gluconeogenesis (IGN) promotes metabolic benefits through activation of a gut‐brain neural axis. However, the local mediator activating gluconeogenic genes in the enterocytes remains unknown. We show that (i) vasoactive intestinal peptide (VIP) signaling through VPAC1 receptor activates the intestinal glucose‐6‐phosphatase gene in vivo, (ii) the activation of IGN by propionate is counteracted by VPAC1 antagonism, and (iii) VIP‐positive intrinsic neurons in the submucosal plexus are increased under the action of propionate. These data support the role of VIP as a local neuromodulator released by intrinsic enteric neurons and responsible for the induction of IGN through a VPAC1 receptor‐dependent mechanism in enterocytes.     

Sensory axon targeting is increased by NGF gene therapy within the lesioned adult femoral nerve

Even though peripheral nerves regenerate well, axons are often misrouted and reinnervate inappropriate distal pathways post-injury. Misrouting most likely occurs at branch points where regenerating axons make choices. Here, we show that the accuracy of sensory axon reinnervation is enhanced by overexpression of the guidance molecule nerve growth factor (NGF) distal to the bifurcation. We used the femoral nerve as a model, which contains both sensory and motor axons that intermingle in the parent trunk and distally segregate into the saphenous (SB) and motor branches (MB). Transection of the parent trunk resulted in misrouting of axon reinnervation to SB and MB. To enhance sensory axon targeting, recombinant adenovirus encoding NGF was injected along the SB close to the bifurcation 1 week post-injury. The accuracy of axon reinnervation was assessed by retrograde tracing at 3 or 8 weeks after nerve injury. NGF overexpression significantly increased the accuracy of SB axon reinnervation to the appropriate nerve branch, in a manner independent of enhancing axon regeneration. This novel finding provides in vivo evidence that gradient expression of neurotrophin can be used to enhance targeting of distal peripheral pathways to increase axon regeneration into the appropriate nerve branch.     

The role of the neuropeptides PACAP and VIP in the photic regulation of gene expression in the suprachiasmatic nucleus

Previously, we have shown that mice deficient in either vasoactive intestinal peptide (VIP) or pituitary adenylate cyclase‐activating polypeptide (PACAP) exhibit specific deficits in the behavioral response of their circadian system to light. In this study, we investigated how the photic regulation of the molecular clock within the suprachiasmatic nucleus (SCN) is altered by the loss of these closely‐related peptides. During the subjective night, the magnitude of the light‐induction of FOS and phosphorylated mitogen‐activated protein kinase (p‐MAPK) immunoreactive cells within the SCN was significantly reduced in both VIP‐ and PACAP‐deficient mice when compared with wild‐type mice. The photic induction of the clock gene Period1 (Per1) in the SCN was reduced in the VIP‐ but not in the PACAP‐deficient mice. Baselines levels of FOS, p‐MAPK or Per1 in the night were not altered by the loss of these peptides. In contrast, during the subjective day, light exposure increased the levels of FOS, p‐MAPK and Per1 in the SCN of VIP‐deficient mice, but not in the other genotypes. During this phase, baseline levels of these markers were reduced in the VIP‐deficient mice compared with untreated controls. Finally, the loss of either neuropeptide reduced the magnitude of the light‐evoked increase in Per1 levels in the adrenals in the subjective night without any change in baseline levels. In summary, our results indicate that both VIP and PACAP regulate the responsiveness of cells within the SCN to the effects of light. Furthermore, VIP, but not PACAP, is required for the appropriate temporal gating of light‐induced gene expression within the SCN.