Identifying novel genes involved in both deer physiological and human pathological osteoporosis

Osteoporosis attacks 10% of the population worldwide. Humans or even the model animals of the disease cannot recover from porous bone. Regeneration in skeletal elements is the unique feature of our newly investigated osteoporosis model, the red deer (Cervus elaphus) stag. Cyclic physiological osteoporosis is a consequence of the annual antler cycle. This phenomenon raises the possibility to identify genes involved in the regulation of bone mineral density on the basis of comparative genomics between deer and human. We compare gene expression activity of osteoporotic and regenerating rib bone samples versus autumn dwell control in red deer by microarray hybridization. Identified genes were tested on human femoral bone tissue from non-osteoporotic controls and patients affected with age-related osteoporosis. Expression data were evaluated by Principal Components Analysis and Canonical Variates Analysis. Separation of patients into a normal and an affected group based on ten formerly known osteoporosis reference genes was significantly improved by expanding the data with newly identified genes. These genes include IGSF4, FABP3, FABP4, FKBP2, TIMP2, TMSB4X, TRIB, and members of the Wnt signaling. This study supports that extensive comparative genomic analyses, here deer and human, provide a novel approach to identify new targets for human diagnostics and therapy. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis

Due to its essential roles in angiogenesis, Notch pathway has emerged as an attractive target for the treatment of pathologic angiogenesis. Although both activation and blockage of Notch signal can impede angiogenesis, activation of Notch signal may be more promising because it was shown that long-term Notch signal blockage resulted in vessel neoplasm. However, an in vivo deliverable Notch ligand with highly efficient Notch-activating capacity has not been developed. Among all the Notch ligands, Delta-like4(Dll4) is specifically involved in angiogenesis. In this study, we generated a novel soluble Notch ligand h D4 R, which consists of the Delta-Serrate-Lag-2 fragment of human Dll4 and an arginine-glycine-aspartate(RGD) motif targeting endothelial cells(ECs). We demonstrated that h D4 R could bind to ECs through its RGD motif and effectively triggered Notch signaling in ECs. Further, we confirmed that h D4 R could suppress angiogenesis in vitro as manifested by network formation assay and sprouting assay. More importantly, h D4 R efficiently repressed neonatal retinal angiogenesis and laser-induced choroidal neovascularization(CNV) as well in vivo. In conclusion, we have developed an in vivo deliverable Notch ligand h D4 R, which suppresses angiogenesis both in vitro and in vivo, thus providing a new approach to tackle excessive angiogenesis relevant disease such as CNV.     

Tau phosphorylation: physiological and pathological consequences

The microtubule-associated protein tau, abundant in neurons, has gained notoriety due to the fact that it is deposited in cells as fibrillar lesions in numerous neurodegenerative diseases, and most notably Alzheimer's disease. Regulation of microtubule dynamics is the most well-recognized function of tau, but it is becoming increasingly evident that tau plays additional roles in the cell. The functions of tau are regulated by site-specific phosphorylation events, which if dysregulated, as they are in the disease state, result in tau dysfunction and mislocalization, which is potentially followed by tau polymerization, neuronal dysfunction and death. Given the increasing evidence that a disruption in the normal phosphorylation state of tau plays a key role in the pathogenic events that occur in Alzheimer's disease and other neurodegenerative conditions, it is of crucial importance that the protein kinases and phosphatases that regulate tau phosphorylation in vivo as well as the signaling cascades that regulate them be identified. This review focuses on recent literature pertaining to the regulation of tau phosphorylation and function in cell culture and animal model systems, and the role that a dysregulation of tau phosphorylation may play in the neuronal dysfunction and death that occur in neurodegenerative diseases that have tau pathology.     

Galectin-9 in physiological and pathological conditions

We first cloned galectin-9 (Gal-9)/ecalectin as a T cell-derived eosinophil chemoattractant. Gal-9 plays a role in not only accumulation but also activation of eosinophils in experimental allergic models and human allergic patients, because Gal-9 induces eosinophil chemoattraction in vitro and in vivo and activates eosinophils in many aspects. Gal-9 requires divalent galactoside-binding activity but not the linker peptide of Gal-9 to exhibit its biological functions, and an unidentified matrix metalloproteinase is involved in the release of Gal-9. Our recent studies also showed that Gal-9 has other functions, such as cell differentiation, aggregation, adhesion, and death. Now, we and other groups are on the way of investigating the regulation and function of Gal-9 in a variety of physiological and pathological conditions. In this article, we will show the possible role of Gal-9 in physiological and pathological conditions by using our recent findings. Published in 2004.     

Galectin-9 in physiological and pathological conditions

We first cloned galectin-9 (Gal-9)/ecalectin as a T cell-derived eosinophil chemoattractant. Gal-9 plays a role in not only accumulation but also activation of eosinophils in experimental allergic models and human allergic patients, because Gal-9 induces eosinophil chemoattraction in vitro and in vivo and activates eosinophils in many aspects. Gal-9 requires divalent galactoside-binding activity but not the linker peptide of Gal-9 to exhibit its biological functions, and an unidentified matrix metalloproteinase is involved in the release of Gal-9. Our recent studies also showed that Gal-9 has other functions, such as cell differentiation, aggregation, adhesion, and death. Now, we and other groups are on the way of investigating the regulation and function of Gal-9 in a variety of physiological and pathological conditions. In this article, we will show the possible role of Gal-9 in physiological and pathological conditions by using our recent findings.     

Glucose transporters: physiological and pathological roles

Glucose is a primary energy source for most cells and an important substrate for many biochemical reactions. As glucose is a need of each and every cell of the body, so are the glucose transporters. Consequently, all cells express these important proteins on their surface. In recent years developments in genetics have shed new light on the types and physiology of various glucose transporters, of which there are two main types—sodium–glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUT)—which can be divided into many more subclasses. Transporters differ in terms of their substrate specificity, distribution and regulatory mechanisms. Glucose transporters have also received much attention as therapeutic targets for various diseases. In this review, we attempt to present a simplified view of this complex topic which may be of interest to researchers involved in biochemical and pharmacological research.     

Effect of myelopeptides on physiological and pathological pain

The action of bone marrow low-molecular peptides (myelopeptides) was studied in the models of physiologic and pathologic pain. Myelopeptides were demonstrated to have a pronounced analgetic effect: they increased the latent period of the rats' response in the hot plate test (physiologic pain) and suppressed severe spinal pain syndrome induced by the generator of pathologically enhanced excitation in the dorsal horn of the spinal cord (pathologic pain). In the experiments with naloxone (an opiate receptor blocker) the data on the opiate properties of myelopeptides were further substantiated. The analgetic effect of myelopeptides can be compared to that of morphine and promedol. Myelopeptides even in considerable doses did not have the side effects characteristic of the majority of opiate analgesics. Therefore, they may be recommended for clinical trials.     

Role of laminins in physiological and pathological angiogenesis

The interaction of endothelial cells and pericytes with their microenvironment, in particular with the basement membrane, plays a crucial role during vasculogenesis and angiogenesis. In this review, we focus on laminins, a major family of extracellular matrix molecules present in basement membranes. Laminins interact with cell surface receptors to trigger intracellular signalling that shapes cell behaviour. Each laminin exerts a distinct effect on endothelial cells and pericytes which largely depends on the adhesion receptor profile expressed on the cell surface. Moreover, proteolytic cleavage of laminins may affect their role in angiogenesis. We report in vitro and in vivo data on laminin-111, -411, -511 and -332 and their associated signalling that regulates cell behaviour and angiogenesis under normal and pathological conditions. We also discuss how tissue-specific deletion of laminin genes affects the behaviour of endothelial cells and pericytes and thus angiogenesis. Finally, we examine how coculture systems with defined laminin expression contribute to our understanding of the roles of laminins in normal and pathological vasculogenesis and angiogenesis.     

Organization of physiological tremors and coordination solutions to postural pointing on an uneven stance surface

The study investigated the destabilization effect on multi-segment physiological tremors and coordinative control for a postural-suprapostural task under different stance conditions. Twenty volunteers executed postural pointing from a level surface and a seesaw balance board; meanwhile, physiological tremors of the whole postural system and fluctuation movements of fingertip/stance surface were recorded. In reference to level stance, seesaw stance led to much fewer tremor increments of the upper limb and less fluctuation movement of the fingertip than tremor increment of the lower limb and rolling movement of the stance surface. Tremor coupling between the adjacent segments organized differentially with stance surface. In reference to level stance, seesaw stance reinforced tremor coupling of the upper limb but enfeebled the coupling in the arm-lumbar and calf-foot complexes. Stance-related differences in physiological tremors could be explained by characteristic changes in the primary and secondary principal components (PC1 and PC2), with relatively high communality with segment tremors of the lower and upper limbs, respectively. Seesaw stance introduced a prominent 4-8Hz spectral peak in PC1 and potentiated 1-4Hz and 8-12Hz spectral peaks of PC2. Structural reorganization of physiological tremors with stance configuration suggests that seesaw stance involves distinct suprapostural and postural synergies for regulating degree of freedom in joint space.     

The measurement of phospholipase A2 activity in human myometrium: physiological and pathological implications

Phospholipase A2 activity was measured in human myometrium obtained at hysterectomy in a group of 41 patients using a double isotope ratio assay based on the liberation of [14-C] oleic acid from 1-palmitoyl-2-[14-C] oleoyl phosphatidylcholine. The enzyme was shown to be calcium independent and to have an optimum pH of 7. There was no significant difference (Mann Whitney U test) in myometrial phospholipase A2 activity between proliferative and secretory phases of the menstrual cycle (ranges: 3.88-30.8 and 0.47-25.85 nmol/mg protein per h respectively) but there was a significant (P less than 0.01) increase in activity in myometrium from uteri with fibroids (median 11.33, range 2.18-30.88 nmol/mg protein per h) compared to those without fibroids (median 6.94, range 0.31-25.85 nmol/mg protein per h). Myometrial phospholipase A2 activity was significantly lower (P less than 0.001) in the 33-40 age group (median 4.71, range 0.31-6.94) compared to the 41-50 age group (median 11.35, range 2.18-30.88 nmol/mg protein per h). In the 51-55 age group phospholipase A2 activity (median 8.71, range 2.5-17.71 nmol/mg protein per h) was not significantly different from that of the other two groups. The increase in activity in the 41-50 age group was not due to the increased incidence of uterine fibroids. These findings suggest that myometrial phospholipase A2 may be important in the pathophysiology of the uterus.     

Consequences of neutrophil adhesion to physiological and pathological targets

The ability of neutrophils to adhere in a coordinated and reversible manner to the endothelium and other tissular components is crucial to their chemoattractant-induced locomotion towards relevant targets. Opsonins play a major role in the killing effect of neutrophils by inducing close adherence between the neutrophil and the target, thus maximizing the effect of the reactive oxygen species released by the stimulated neutrophils. Reactive oxygen species are released together with degradative enzymes and other killing proteins associated with neutrophil degranulation. This targeted neutrophil activity kills invading microorganisms but, in a similar way, may be harmful to organs, cells and molecules that have been altered in some way or are involved in immune reactions. In some other pathological situations where body fluids contain proinflammatory agents, neutrophils may behave in a nontargeted and inappropriate manner. In such cases, adherence is often increased, thus slowing locomotion. Moreover, inflammatory agents often prime neutrophils for the oxidative burst induced by chemoattractants or other stimuli. The combined slow locomotion and hypersensitivity of primed neutrophils leads to a premature release of killing substances which may affect blood components, vascular cells, connective tissue or whole organs. Any disturbance of neutrophil adherence is thus potentially harmful and must be recognized and suitably treated.     

Origin of the human hand

A means of determining the phylogenetic implications of similarities between the hands of man and non-human primates is proposed. The only traits shared by man and non-human primates accepted as evidence of our ancestral hand structure and functions are those which are incompatible or out of keeping with current behavior of the human hand. They may be assumed to remain only as relics of adaptations to former habits of locomotion and feeding. The relics found through this analysis are all traits that are present in the apes (some of them only in African apes) and probably related to functions of the hand in suspension of the body, fist-walking, and knuckle-walking. The presence of these traits in man implies that human ancestors similarly used the hand to suspend the body in the trees and to support it on the back of the flexed fingers.     

Endothelin-1: physiological and pathological roles in myometrium

Endothelin-1 (ET-1), a member of endothelin peptide family is released by many different tissues including uterine smooth muscle. ET-1 acts through ETA and ETB receptors and is implicated in a wide range of biological and pathological functions that explain the great attention of the pharmacological industry for ET-1 receptors as potential therapeutic targets in vascular pathologies and cancers. It is now well established that ET-1 is also able to regulate myometrial functions. In the present review, we focused on ET axis and related signaling pathways involved in the regulation of myometrial contraction, as well as cell proliferation and survival. Such ET-1-mediated cellular functions play a critical role in normal pregnancy, preterm birth and uterine leiomyoma.