Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD.

It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to Aß-peptides and prevent Aß aggregation. We have previously shown that treatment of Alzheimer's Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of 131I-labeled IDIF and 131I- and 124I-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher Aß-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice.

Effects of early postoperative enteral nutrition versus usual care on serum albumin, prealbumin, transferrin, time to first flatus and postoperative hospital stay for patients with colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Early enteral nutrition (EEN) after surgery had been reported to decrease morbidity and mortality. However, no meta-analysis performed on nutrition status and recovery after surgery to Colorectal cancer (CRC). AIM: We aimed to estimate effect of EEN for postoperative CRC. METHODS: Electronic databases were searched for randomized controlled trials published prior to September 2017. Papers comparing EEN after surgery to traditional nutritional regimen in CRC patients were selected. The chosen articles should containe one or more of the following outcome measures: serum albumin, prealbumin, transferrin, time to first flatus and postoperative hospital stay. RESULTS: 2307 cases from 26 studies were included. The analysis showed that EEN was more effective in increasing serum albumin and prealbumin, promoting the recovery of gastrointestinal function, and decreasing the time of postoperative hospital stay, especially for colon cancer. CONCLUSION: EEN can improve nutritional status and promote intestinal function recovery for patients undergoing CRC surgery.

Central transthyretin acts to decrease food intake and body weight.

Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities.

Impact of Preoperative Prealbumin on Outcomes After Cardiac Surgery.

BACKGROUND: Preoperative malnutrition is increasingly prevalent in patients undergoing cardiac surgery. Although prealbumin is a widely used indicator of nutrition status, its use in the preoperative assessment of patients undergoing cardiac surgery is not well defined. The purpose of this study is to determine the impact of preoperative prealbumin levels on outcomes after cardiac surgery. MATERIALS AND METHODS: Data were prospectively gathered from February 2013 to July 2013 on 69 patients undergoing cardiac surgery. Prealbumin levels were obtained within 24 hours of surgery. Patients were divided into 2 groups based on a prealbumin cutoff value of 20 mg/dL. RESULTS: Of the 69 patients, 32 (46.4%) had a preoperative prealbumin ≤ 20 mg/dL. There was no correlation between prealbumin levels and body mass index (r = -0.13, P = .28). Likewise, there was no correlation between preoperative albumin and prealbumin levels (r = 0.09, P = .44). Nine of 32 (28.1%) patients with low preoperative prealbumin levels had postoperative infections compared with 2 of 37 (5.4%) patients with high prealbumin levels (P = .010). Patients with low prealbumin levels also had increased risk of postoperative intubation for > 12 hours (P = .010). CONCLUSIONS: Patients undergoing cardiac surgery with preoperative prealbumin levels of ≤ 20 mg/dL have an increased risk for postoperative infections and the need for longer mechanical ventilation. If feasible, nutrition optimization of such patients may be considered prior to cardiac surgery.

Immunization in familial amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant.

The mechanism of amyloid formation in familial amyloidotic polyneuropathy (FAP), a hereditary disorder associated with mutant transthyretin (TTR), is still unknown. It is generally believed that altered conformations exposing cryptic regions are intermediary steps in this mechanism. A TTR mutant--Y78F (transthyretin mutant with phenylalanine replacing tyrosine at position 78)--designed to destabilize the native structure has been shown to expose a cryptic epitope recognized by a monoclonal antibody that reacts only with highly amyloidogenic mutants presenting the amyloid fold or with amyloid fibrils. To test whether TTR deposition in FAP can be counteracted by antibodies for cryptic epitopes, we immunized with TTR Y78F, transgenic mice carrying the most common FAP-associated TTR mutant--V30M (transthyretin mutant with methionine replacing valine at position 30)--at selected ages that present normally with either nonfibrillar or TTR amyloid deposition. Compared to age-matched control nonimmunized mice, Y78F-immunized mice had a significant reduction in TTR deposition usually found in this strain, in particular in stomach and intestine; by contrast, animals immunized with V30M did not show differences in deposition in comparison with nonimmunized mice. Immunohistochemical analyses of tissues revealed that immunization with Y78F lead to infiltration by lymphocytes and macrophages at common deposition sites, but not in tissues such as liver, choroid plexus, and Langerhans islets, in which TTR is produced. These results suggest that Y78F induced production of an antibody that reacts specifically with deposits and leads to an immune response effective in removing/preventing TTR deposition. Therefore, TTR immunization with selected TTR mutants has potential application in immune therapy for FAP.

Down regulation of a harmful variant protein by replacement of its normal protein.

To compensate for the hypoprotein and hypoalbuminemia of familial amyloidotic polyneuropathy (FAP) patients, 800 ml of fresh frozen plasma (FFP) was intravenously administered and change in total and variant transthyretin (TTR) levels were measured in the plasma. After injection of FFP, total plasma TTR levels were elevated and variant TTR levels decreased from 24 to 48 h, accompanied by an elevation of plasma total protein, albumin levels and TTR levels. To elucidate the mechanism of this phenomenon, a large amount of purified normal TTR from normal human plasma was intravenously injected in mice and FAP patients. By intravenous injection of 3 mg of the purified TTR to C57Black6, the expression of TTR mRNA decreased from 6 to 24 h post injection, and gradually increased up to 48 h post injection. After injecting 400 mg of normal TTR in each of 3 FAP patients, total plasma TTR levels were elevated and variant TTR levels decreased significantly from 24 to 48 h. These results suggested that down regulation of the harmful protein by replacement of its normal form of the protein occurred by this method. This phenomenon should be applied as the basis for one of the useful methods for decreasing the harmful proteins in the circulation.