In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson’s disease, ...and Alzheimer’s disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called “cheese effect.” Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.
Aim
Phase angle (PhA) can be determined through bioelectrical impedance analysis and is a unique variable for skeletal muscle. The objective of this study was to evaluate the relationship between PhA ...and muscle mass/quality in older adults. In addition, we attempted to determine the cutoff value of PhA for poor muscle function.
Methods
Community-dwelling Japanese older men (n=285, 81.1±7.1 years) and women (n=724, 80.4±6.8 years) participated in this study and were classified into four groups based on the Asian Working Group for Sarcopenia (normal, presarcopenia, dynapenia, and sarcopenia). We measured PhA using bioelectrical impedance analysis, muscle quantity and quality indicators using ultrasonography, muscle strength, and physical performance and compared them in four groups. We also tried to determine the cutoff value of PhA for poor muscle function.
Results
We found a significant difference in PhA among the four groups in men (P<0.05), and the dynapenia (3.61±0.75°) and sarcopenia groups (3.40±0.74°) showed significantly lower values than the normal group (4.50±0.86°) (P<0.05), but not the presarcopenia group (4.12±0.85°). In women, a significant difference was also observed among the four groups (P<0.05), and the dynapenia (3.41±0.65°) and sarcopenia groups (3.31±0.66°) showed significantly lower measures than the normal group (4.14±0.71°) (P<0.05), but not the presarcopenia group (4.07±0.51°). The receiver-operating characteristic curve analysis indicated the best cutoff value of PhA (men: 4.05°, women: 3.55°) to discriminate sarcopenia and dynapenia from normal and presarcopenia.
Conclusion
These findings suggest that PhA is a useful indicator for muscle function.
Cell migration in 3D matrix Even-Ram, Sharona; Yamada, Kenneth M
Current opinion in cell biology,
10/2005, Letnik:
17, Številka:
5
Journal Article
Recenzirano
The ability of cells to migrate within the extracellular matrix and to remodel it depends as much on the physical and biochemical characteristics of a particular matrix as on cellular properties. ...Analyzing the different modes of migration of cells in matrices, and how cells switch between these modes, is vital for understanding a variety of physiological and pathological processes. Recent work provides new insights, but also raises some debates about the mechanisms and regulation of cell migration in three-dimensional matrices.
To adhere and migrate, cells must be capable of applying cytoskeletal force to the extracellular matrix (ECM) through integrin receptors. However, it is unclear if connections between integrins and ...the ECM are immediately capable of transducing cytoskeletal contraction into migration force, or whether engagement of force transmission requires maturation of the adhesion. Here, we show that initial integrin-ECM adhesions become capable of exerting migration force with the recruitment of vinculin, a marker for focal complexes, which are precursors of focal adhesions. We are able to induce the development of focal complexes by the application of mechanical force to fibronectin receptors from inside or outside the cell, and we are able to extend focal complex formation to vitronectin receptors by the removal of c-Src. These results indicate that cells use mechanical force as a signal to strengthen initial integrin-ECM adhesions into focal complexes and regulate the amount of migration force applied to individual adhesions at localized regions of the advancing lamella.
Many organs, including salivary glands, lung and kidney, are formed during embryonic development by epithelial branching. In branching morphogenesis, repetitive epithelial cleft and bud formation ...create the complex three-dimensional branching structures characteristic of many organs. Although the mechanisms are poorly understood, one might involve the site-specific accumulation of some regulatory protein. Here we show that the extracellular matrix protein fibronectin is essential for cleft formation during the initiation of epithelial branching. Fibronectin messenger RNA and fibrils appeared transiently and focally in forming cleft regions of submandibular salivary-gland epithelia, accompanied by an adjacent loss of cadherin localization. Decreasing the fibronectin concentration by using small interfering RNA and inhibition by anti-fibronectin or anti-integrin antibodies blocked cleft formation and branching. Exogenous fibronectin accelerated cleft formation and branching. Similar effects of fibronectin suppression and augmentation were observed in developing lung and kidney. Mechanistic studies revealed that fibrillar fibronectin can induce cell-matrix adhesions on cultured human salivary epithelial cells with a local loss of cadherins at cell-cell junctions. Thus, fibronectin expression is required for cleft formation in branching morphogenesis associated with the conversion of cell-cell adhesions to cell-matrix adhesions.
Nesfatin-1 is a novel satiety molecule in the hypothalamus and is also present in peripheral tissues. Here we sought to identify the active segment of nesfatin-1 and to determine the mechanisms of ...its action after peripheral administration in mice. Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner. Nesfatin-1 has three distinct segments; we tested the effect of each segment on food intake. Injection of the midsegment decreased food intake under leptin-resistant conditions such as db/db mice and mice fed a high-fat diet. After injection of the midsegment, expression of c-Fos was significantly activated in the brainstem nucleus tractus solitarius (NTS) but not in the hypothalamic arcuate nucleus; the nicotinic cholinergic pathway to the NTS contributed to midsegment-induced anorexia. Midsegment injection significantly increased expression of proopiomelanocortin and cocaine- and amphetamine-regulated transcript genes in the NTS but not in the arcuate nucleus. Investigation of mutant midsegments demonstrated that a region with amino acid sequence similarity to the active site of agouti-related peptide was indispensable for anorexigenic induction. Our findings indicate that the midsegment of nesfatin-1 causes anorexia, possibly by activating POMC and CART neurons in the NTS via a leptin-independent mechanism after peripheral stimulation.
Peripherally administered nesfatin-1 and its mid-segment suppress food intake in mice. The nicotinic cholinergic pathway to the nucleus tractus solitarius contributes to the anorexigenic action of the mid-segment.
Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has traditionally been defined by its role as a binding protein and its association with IGF delivery and availability. Development of ...non-IGF binding IGFBP-3 analogs and the use of cell lines devoid of type 1 IGF receptors (IGF-R) have led to critical advances in the field of IGFBP-3 biology. These studies show that IGFBP-3 has IGF-independent roles in inhibiting cell proliferation in cancer cell lines. Nuclear transcription factor, retinoid X receptor (RXR)-alpha, and IGFBP-3 functionally interact to reduce prostate tumor growth and prostate-specific antigen in vivo. Moreover, IGFBP-3 inhibits insulin-stimulated glucose uptake into adipocytes independent of IGF. The purpose of this review is to highlight IGFBP-3 as a novel effector molecule and not just another "binding protein" by discussing its IGF-independent actions on metabolism and cell growth. Although this review presents studies that assume the role of IGFBP-3 as either an endocrine or autocrine/paracrine molecule, these systems may not exist as distinct entities, justifying the examination of IGFBP-3 in an integrated model. Also, we provide an overview of factors that regulate IGFBP-3 availability, including its production, methylation, and ubiquitination. We conclude with the role of IGFBP-3 in whole body systems and possible future applications of IGFBP-3 in physiology.
Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem.
is a particularly difficult pathogen to treat effectively ...because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log
CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden
infections and requires further study.
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