Parathyroid hormone and its analogues--molecular mechanisms of action and efficacy in osteoporosis therapy

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.     

保幼激素的分子作用机制

蜕皮激素(ecdysteroids, Ecd)和保幼激素(juvenile hormone, JH)是调控昆虫发育和变态的两种最为重要的昆虫激素。尽管Ecd的分子作用机制已经相当明了,但是,因为迄今为止还没有成功地鉴定出JH受体,人们对JH的分子作用机制还了解甚少。本文从三个方面较为详尽地介绍了近年来JH分子作用机制的相关研究进展：1) JH和Ecd在分子水平上相互作用, JH可以通过改变或者抑制Ecd信号来调控昆虫的发育和变态;2) JH核受体的两个候选基因为Met和USP;3) JH还可以通过膜受体和蛋白激酶C传导信号。     

保幼激素的分子作用机制研究

保幼激素(juvenile hormone,JH)和蜕皮激素(20-hydroxyecdysone,20E)是协同调控昆虫发育、变态与生殖的两个重要激素。由于20E的主要分子作用机制已经比较明了,揭示JH的分子作用机制成为过去20多年来昆虫学领域研究的一个重点和难点。国内外多个研究团队利用赤拟谷盗Tribolium castaneum、果蝇Drosophilamelanogaster、烟草天蛾Manduca sexta等为模式,在JH受体的鉴定、JH在昆虫发育变态和生殖中的分子调控机制以及JH与20E在分子水平上的交互作用等方面开展了大量的研究工作,本文就近几年在这些方面取得的主要研究进展作一个综述。     

Thyroid hormone analogues potentiate the antiviral action of interferon-γ by two mechanisms

L-thyroxine (L-T₄) potentiates the antiviral activity of human interferon-γ (IFN-γ) in HeLa cells. We have added thyroid hormone and analogues to cells either 1) for 24 h pretreatment prior to 24 h of IFN-γ (1.0 IU/ml), 2) for 24 h cotreatment with IFN-γ, 3) for 4 h, after 20 h cell incubation with IFN-γ, alone, or 4) for 24 h pretreatment and 24 h cotreatment with IFN-γ. The antiviral effect of IFN-γ was then assayed. L-T₄ potentiated the antiviral action of IFN-γ by a reduction in virus yield of more than two logs, the equivalent of a more than 100-fold potentiation of the IFN's antiviral effect. 3,3′,5-L-triiodothyronine (L-T₃) was as effective as L-T₄ when coincubated for 24 h with IFN-γ but was less effective than L-T₄ when coincubated for only 4 h. D-T₄, D-T₃, 3,3′,5-triiodothyroacetic acid (triac), tetraiodothyroacetic acid (tetrac), and 3,5-diiodothyronine (T₂) were inactive. When preincubated with L-T₄ for 24 h prior to IFN-γ treatment, tetrac blocked L-T₄ potentiation, but, when coincubated with L-T₄ for 4 h after 20 h IFN-γ, tetrac did not inhibit the L-T₄ effect. 3,3′,5′-L-triiodothyronine (rT₃) also potentiated the antiviral action of IFN-γ, but only in the preincubation model. Furthermore, the effects of rT₃ preincubation and L-T₃ coincubation were additive, resulting in 100-fold potentiation of the IFN-γ effect. When L-T₄, L-T₃, or rT₃, plus cycloheximide (5 μg/ml), was added to cells for 24 h and then removed prior to 24 h IFN-γ exposure, the potentiating effect of the three iodothyronines was completely inhibited. In contrast, IFN-γ potentiation by 4 h of L-T₄ or L-T₃ coincubation was not inhibited by cycloheximide (25 μg/ml). These studies demonstrate two mechanisms by which thyroid hormone can potentiate IFN-γ's effect: 1) a protein synthesis-dependent mechanism evidenced by enhancement of IFN-γ's antiviral action by L-T₄, L-T₃, or rT₃ preincubation, and inhibition of enhancement by tetrac and cycloheximide, and 2) a protein synthesis-independent (posttranslational) mechanism, not inhibited by tetrac or cycloheximide, demonstrated by 4 h coincubation of L-T₄ or L-T₃, but not rT₃, with IFN-γ. The protein synthesis-dependent pathway is responsive to rT₃, a thyroid hormone analogue generally thought to have little effect on protein synthesis. A posttranslational mechanism by which the antiviral action of IFN-γ can be regulated has not previously been described. © 1996 Wiley-Liss, Inc.     

Parathyroid hormone versus bisphosphonate treatment on bone mineral density in osteoporosis therapy: a meta-analysis of randomized controlled trials

Background

Bisphosphonates and parathyroid hormone (PTH) represent the antiresorptive and anabolic classes of drugs for osteoporosis treatment. Bone mineral density (BMD) is an essential parameter for the evaluation of anti-osteoporotic drugs. The aim of this study was to evaluate the effects of PTH versus bisphosphonates on BMD for the treatment of osteoporosis.

Methods/Principal Findings

We performed a literature search to identify studies that investigated the effects of PTH versus bisphosphonates treatment on BMD. A total of 7 articles were included in this study, representing data on 944 subjects. The pooled data showed that the percent change of increased BMD in the spine is higher with PTH compared to bisphosphonates (WMD = 5.90, 95% CI: 3.69–8.10, p<0.01,). In the hip, high dose (40 µg) PTH (1–34) showed significantly higher increments of BMD compared to alendronate (femoral neck: WMD = 5.67, 95% CI: 3.47–7.87, p<0.01; total hip: WMD = 2.40, 95%CI: 0.49–4.31, p<0.05). PTH treatment has yielded significantly higher increments than bisphosphonates with a duration of over 12 months (femoral neck: WMD = 5.67, 95% CI: 3.47–7.86, p<0.01; total hip: WMD = 2.40, 95% CI: 0.49–4.31, P<0.05) and significantly lower increments at 12 months (femoral neck: WMD = −1.05, 95% CI: −2.26–0.16, p<0.01; total hip: WMD: −1.69, 95% CI: −3.05–0.34, p<0.05). In the distal radius, a reduction in BMD was significant between PTH and alendronate treatment. (WMD = −3.68, 95% CI: −5.57–1.79, p<0.01).

Discussion

Our results demonstrated that PTH significantly increased lumbar spine BMD as compared to treatment with bisphosphonates and PTH treatment induced duration- and dose-dependent increases in hip BMD as compared to bisphosphonates treatment. This study has also disclosed that for the distal radius, BMD was significantly lower from PTH treatment than alendronate treatment.     

Antibacterials - mechanisms of action

Recent studies on antibacterials have focused on the development of antimycobacterial agents and antibacterial peptides, and on furthering the understanding of agents that have been available for several decades, including imidazoles, beta-lactams and quinolones. New areas of research include antisense oligonucleotides, antibacterial peptides and a new class of agents, oxazolidinones.     

Aldosterone: the mechanisms of molecular action

Aldosterone: a steroid hormone of adrenal cortex, has recently attracted much interest not only due to its great importance in regulation of salt and water balance, but also because of its key role in therapy of cardiovascular and renal pathology. The classical genomic mechanism of molecular action of aldosterone is mediated through interaction with mineral-corticoid receptors. Fast nongenomic pathway of cell signal transduction begins with interaction with hypothetic membrane receptors and includes activation of different kinase cascades. Interference of these two pathways of signal transduction assures abroad spectrum of aldosterone effects depending on the cell type, and also secures multycomponent regulation depending on the need of specific functional and stress situation. This review is dedicated to modern views of mechanisms of aldosterone molecular action, mostly of the level of aldosterone-sensitive segment of kidney nephron.     

Interaction of secretin5-27 and its analogues with hormone receptors on pancreatic acini.

The C-terminal tricosapeptide of secretin (S5-27) and two analogues, one with asparagine replacing aspartic acid in position 15 (15-Asn-S5--27) and one with lysine replacing aspartic acid in position 15 (15-Lys-S5-27) were tested for their abilities to interact with hormone receptors on pancreatic acinar cells. In interacting with the receptors which prefer vasoactive intestinal peptide (vasoactive intestinal peptide-preferring receptors), the apparent affinity of 15-Asn S5-27 was equal to that of 15-Lys-S5-27 and was greater than that of S5-27. In interacting with secretin-preferring receptors, the apparent affinity of 15-Asn-S5--27 was equal to that of S5-27 and was greater than that of 15-Lys-S5-27. In interacting with the secretin-preferring receptors each of the secretin fragments was approximately 2% as effective as secretin in causing an increase in cellular cyclic AMP. None of these fragments was able to cause a detectable increase in cyclic AMP mediated by the vasoactive intestinal peptide-preferring receptors. The dose vs. response curves for the action of secretin and vasoactive intestinal peptide on cellular cyclic AMP and on amylase secretion as well as the pattern of effects of secretin fragments on these actions indicated that the increase in amylase secretion caused by vasoactive intestinal peptide and secretin is mediated exclusively by the vasoactive intestinal peptide-preferring receptors. Furthermore, occupation of approximately 50% of the vasoactive intestinal peptide-preferring receptors is sufficient to cause maximal stimulation of amylase secretion.