Summary Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP Receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa-B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotics. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH’s therapeutic action through its ability to direct mesenchymal cell fate.

Reactive oxygen species such as superoxide anion radicals (O2 (-) ) and hydrogen peroxide (H2 O2 ) have for long time been recognized as undesirable by-products of the oxidative mitochondrial generation of adenosine triphosphate (ATP). Recently, these highly reactive species have been associated to important signaling pathways in diverse physiological conditions such as those activated in hypoxic microenvironments. The molecular response to hypoxia requires fast-acting mechanisms acting within a wide range of partial pressures of oxygen (O2 ). Intracellular O2 sensing is an evolutionary preserved feature, and the best characterized molecular responses to hypoxia are mediated through transcriptional activation. The transcription factor, hypoxia-inducible factor 1 (HIF-1), is a critical mediator of these adaptive responses, and its activation by hypoxia involves O2 -dependent posttranslational modifications and nuclear translocation. Through the induction of the expression of its target genes, HIF-1 coordinately regulates tissue O2 supply and energetic metabolism. Other transcription factors such as nuclear factor κB are also redox sensitive and are activated in pro-oxidant and hypoxic conditions. The purpose of this review is to summarize new developments in HIF-mediated O2 sensing mechanisms and their interactions with reactive oxygen species-generating pathways in normal and abnormal physiology.

Since the 1970s, the establishment and development of the biotech industry has improved exponentially, allowing the commercial production of biopharmaceutical proteins. Nowadays, new recombinant protein production is considered a multibillion-dollar market, in which about 25% of commercial pharmaceuticals are biopharmaceuticals. But to achieve a competitive production process is not an easy task. Any production process has to be highly productive, efficient and economic. Despite that the perfect host is still not discovered, several research groups have chosen Pichia pastoris as expression system for the production of their protein because of its many features. The attempt of this review is to embrace several research lines that have adopted Pichia pastoris as their expression system to produce a protein on an industrial scale in the health care industry.

In the past two decades, Chile has developed intense mining activity in the Andes mountain range, whose altitude is over 4,000 meters above sea level. It is estimated that a workforce population of over 55,000 is exposed to high altitude hypobaric hypoxia. The miners work under shift systems which vary from 4 to 20 days at the worksite followed by rest days at sea level, in a cycle repeated for several years. This Chronic Intermittent Hypoxia (CIH) constitutes an unusual condition for workers involving a series of changes at the physiological, cellular and molecular levels attempting to compensate for the decrease in the environmental partial pressure of oxygen (PO 2 ). The mine worker must become acclimatized to CIH, and consequently undergoes an acute acclimatization process when he reaches the worksite and an acute reverse process when he reaches sea level. We have observed that after a period of 3 to 8 years of CIH exposure workers acclimatize well, and evidence from our studies and those of others indicates that CIH induces acute and chronic multisystem adjustments which are eff ective in off setting the reduced availability of oxygen at high altitudes. The aims of this review are to summarize fi ndings of the physiological responses to CIH exposure, highlighting outstanding issues in the fi eld.

The development of sperm cryopreservation has enabled transcendental changes to occur in the reproductive biotechnology of both mammals and fish; it has become a basic tool for animal improvement. Nevertheless, these protocols cause damage to cell structure and physiology, altering sperm functioning due to cryoinjuries during freezing and thawing. However, studies of the effects on the structural, functional and genomic stability of the mitochondria in fish spermatozoa during cryopreservation are still lacking. The object of this review was to analyse the effect of cryopreservation on mitochondrial metabolic pathways in fish spermatozoa. This effect is related with the bioenergy mechanism for flagellar movement during the activation of sperm motility. In teleost fish, the mitochondria may be cylindrical, spherical or irregular in shape and adhere in a helicoidal or conical pattern to the middle piece. The salmonidae have only a single mitochondrion, but this may vary in other species; the mitochondria provide the flagellum with energy during sperm motility, when sperm respiration is essential. The effects of cryopreservation can induce structural damage to the mitochondria, altering the biochemical process involved in ATP production and thus causing a reduction in sperm motility. Fragmentation damage to nuclear DNA and diminution in sperm motility is mainly associated with damage to the structure and metabolic functioning of the mitochondrion. A direct correlation exists between the mitochondrial membrane potential (transmembrane integrity, ΔΨ m ) and the motility and fertilizing capacity of the cryopreserved spermatozoa, confirming that this organelle is the energy nucleus of the spermatozoon and that the cessation or prolongation of motility and successful fertilization depend on the availability of ATP in the spermatozoa. Further works are need to incorporate biotechnology studies, at cell and molecular level, of the possible effects of cryopreservation on mitochondrial DNA, enzymatic or metabolic modifications of the citric acid cycle, and the oxidative phosphorylation process in the inner membrane, as well as studies of the mitochondrial ultrastructure. Thus, mitochondrial dynamics could be established as a potential target for therapeutic strategies.

Exposure to hypobaric hypoxia causes oxidative damage to male rat reproductive function. The aim of this study was to evaluate the protective effect of a blueberry extract (BB-4) in testis of rats exposed to hypobaric hypoxia. Morphometric analysis, cellular DNA fragmentation, glutathione reductase (GR), and superoxide dismutase (SOD) activities were evaluated. Our results showed that supplementation of BB-4 reduced lipid peroxidation, decreased apoptosis, and increased GR and SOD activities in rat testis under hypobaric hypoxia conditions (P < 0.05). Therefore, this study demonstrates that blueberry extract significantly reduced the harmful effects of oxidative stress caused by hypobaric hypoxia in rat testis by affecting glutathione reductase and superoxide dismutase activities.

Abstract. Despite continuous advances in the knowledge of breast cancer pathophysiology, this type of neoplasia remains a leading cause of cancer-related death in women worldwide. Carcinogenesis takes a progressive course from somatic mutations, alteration of the DNA repair mechanisms, inhibition of growth suppressors, followed by cell proliferation, tissue invasion and risk of metastasis. Less than 10% of all cancers are hereditary, and in the case of breast cancer only 8%, a phenomenon linked to genetic changes in BRCA1 or BRCA2. All the other cancers can be caused by an infection (15%) or in most cases (75%) the etiology is unknown. Patients with genetic mutations in BRCA1 or BRCA2 have 30-60% likelihood of developing a second primary breast cancer and between 11 and 45% risk of ovarian cancer, HER-2/neu is overexpressed in ~30% of human breast tumors and it has a predictive role in chemotherapy and endocrine therapy.

In Chile, due to the intensive activity developed in confining areas of the Andes Mountains ranging in altitude over 4000 asl, there has been an increasing intermittent movement of human resources to high altitude conditions. This unusual condition, defined as hypobaric hypoxia, affects notoriously in any living organism and there shows a series of physiological responses. Studies performed in rats under chronic hypobaric hypoxia and intermittent hypobaric hypoxia have registered changes in testicular morphology together with loss of spermatogenic cells in all stages of spermatogenic cycle. Furthermore, recent tests reinforced the existence of an oxidative metabolism in epididymis of rats subjected to hypobaric hypoxia due to the increase in the regulator enzyme expression of reactive oxygen species (ROS), This increase in the production of ROS induced a rise in apoptosis at germinal cell level, leading to a state of hypo-spermatogenesis that may jeopardise masculine fertility. Therefore, the eventual development of oxidative stress in spermatogenic cells and consequently the spermatozoids of workers subjected to high altitude, either chronic or intermittent, turns out to be critical when it poses as an imminent risk to the viability and quality of the reproductive cells of workers subjected to intermittent hypobaric hypoxia.