It is well known that thyroid hormone affects body composition; however, the effect of the thyroid hormone receptor β (TRβ)-selective thyromimetic GC-1 on this biological feature had not been demonstrated. In the current study, we compared the effects of a 6-week treatment with triiodothyronine (T3; daily injections of 3 or 6 μg/100 g body weight) or GC-1 (equimolar doses) on different metabolic parameters in adult female rats. Whereas all animals gained weight (17–25 g) in a way not basically affected by T3 or GC-1 treatment, only T3 treatment selectively increased food intake (50–70%). Oxygen consumption was significantly and equally increased (50–70%) by T3 and GC-1. Analysis of body composition by dual-energy X-ray absorptiometry (DEXA) revealed that, whereas control animals gained about 80% of fat mass, T3- or GC-1-treated animals lost 70–90 and ~20% respectively. Direct analysis of the carcass showed that T3 treatment promoted a 14–74% decrease in fat content but GC-1 treatment promoted only a 15–23% reduction. The gain in lean mass by DEXA and the carcass protein content were not affected by T3 or GC-1 treatment. However, the mass of individual skeletal muscles was negatively affected by T3 but only barely by GC-1. These findings highlight the potential use of GC-1 for the treatment of obesity and the metabolic syndrome.

Several drug delivery systems have been proposed to overcome physiological barriers, improving ocular bioavailability. Systemic routes are seldom used due to the blood-ocular barrier. Novel drug delivery systems based on nanotechnology techniques have been developed to overcome ocular physiological barriers. This non-systematic review suggests the utilization of a transitory blood-ocular breakdown to allow the access of drugs by nanotechnology drug delivery systems via the systemic route. We discuss the possible ways to cause the breakdown of the blood-ocular barrier: acute inflammation caused by intraocular surgery, induced ocular hypotony, and the use of inflammatory mediators. The suitability of use of the systemic route and its toxic effects are also discussed in this article.

Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via β₂-adrenoceptor (β2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, α_2A-AR and α_2C-AR (α_2A/α_2C-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α_2A/α_2C-ARKO versus wild-type (WT) mice, micro–computed tomographic (µCT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-κB (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine–regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial β₂-AR mRNA expression also was similar in KO and WT littermates, whereas α_2A-, α_2B- and α_2C-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected α_2A-, α_2B-, α_2C- and β₂-ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective α₂-AR agonist clonidine and to the nonspecific α-AR antagonist phentolamine. These findings suggest that β₂-AR is not the single adrenoceptor involved in bone turnover regulation and show that α₂-AR signaling also may mediate the SNS actions in the skeleton. © 2010 American Society for Bone and Mineral Research. © 2011 American Society for Bone and Mineral Research.

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.

Thyrotoxicosis is frequently associated with increased bone turnover and decreased bone mass. To investigate the role of thyroid hormone receptor-β (TRβ) in mediating the osteopenic effects of triiodothyronine (T₃), female adult rats were treated daily (64 days) with GC-1 (1.5 μg/100 g body wt), a TRβ-selective thyromimetic compound. Bone mass was studied by dual-energy X-ray absorptiometry of several skeletal sites and histomorphometry of distal femur, and the results were compared with T₃-treated (3 μg/100 g body wt) or control animals. As expected, treatment with T₃significantly reduced bone mineral density (BMD) in the lumbar vertebrae (L₂-L₅), femur, and tibia by 10–15%. In contrast, GC-1 treatment did not affect the BMD in any of the skeletal sites studied. The efficacy of GC-1 treatment was verified by a reduction in serum TSH (–52% vs. control, P < 0.05) and cholesterol (–21% vs. control, P < 0.05). The histomorphometric analysis of the distal femur indicated that T₃but not GC-1 treatment reduced the trabecular volume, thickness, and number. We conclude that chronic, selective activation of the TRβ isoform does not result in bone loss typical of T₃-induced thyrotoxicosis, suggesting that the TRβ isoform is not critical in this process. In addition, our findings suggest that the development of TR-selective T₃analogs that spare bone mass represents a significant improvement toward long-term TSH-suppressive therapy.