Andrea B. Zepeda

The Hypoxic Testicle: Physiology and Pathophysiology

Mammalian spermatogenesis is a complex biological process occurring in the seminiferous tubules in the testis. This process represents a delicate balance between cell proliferation, differentiation, and apoptosis. In most mammals, the testicles are kept in the scrotum 2 to 7°C below body core temperature, and the spermatogenic process proceeds with a blood and oxygen supply that is fairly independent of changes in other vascular beds in the body. Despite this apparently well-controlled local environment, pathologies such as varicocele or testicular torsion and environmental exposure to low oxygen (hypoxia) can result in changes in blood flow, nutrients, and oxygen supply along with an increased local temperature that may induce adverse effects on Leydig cell function and spermatogenesis. These conditions may lead to male subfertility or infertility. Our literature analyses and our own results suggest that conditions such as germ cell apoptosis and DNA damage are common features in hypoxia and varicocele and testicular torsion. Furthermore, oxidative damage seems to be present in these conditions during the initiation stages of germ cell damage and apoptosis. Other mechanisms like membrane-bound metalloproteinases and phospholipase A2 activation could also be part of the pathophysiological consequences of testicular hypoxia.

Cellular and molecular mechanisms in the hypoxic tissue: role of HIF-1 and ROS

Reactive oxygen species such as superoxide anion radicals (O2−) and hydrogen peroxide (H2O2) 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. Copyright

Oxidative Stress in Rat Testis and Epididymis Under Intermittent Hypobaric Hypoxia: Protective Role of Ascorbate Supplementation

Hypobaric hypoxia (HH), an environmental condition of high altitude encountered by mountaineers, miners, and observatory, rural health, border patrol, and rural education workers, jeopardizes normal physiologic functions in humans. The present study was conducted to evaluate the effects of intermittent HH (IHH; equivalent to 4600 m above mean sea level) on oxidative stress and the protective role of dietary ascorbic acid on rat testis and epididymis. Ten-week-old male Wistar rats were assigned to 1 of 6 groups: 1) normobaric (Nx), 2) Nx + physiologic solution (Nx + PS), 3) Nx + ascorbic acid (Nx + AA), 4) IHH, 5) IHH + PS, or 6) IHH + AA. Animals subjected to IHH were exposed for 96 hours followed by normobaric conditions for 96 hours for a total of 32 days. The control groups (2 and 5) were injected with doses of PS, and the treated groups (3 and 6) were injected with doses of AA (10 mg x kg(-1) body weight) at an interval of 96 hours. Rats were sacrificed on day 32 after initiation of the protocol. The testis and epididymis were collected to determine the activity and expression of glutathione reductase and the levels of lipid peroxide formation. An epididymal sperm count was also performed in each animal. The results of this study revealed that IHH induced lipid peroxidation, a reduction in glutathione reductase activity in testis and epididymis, and a significant decrease in epididymal sperm count. Treatment with AA prevented these changes. In conclusion, AA was capable of decreasing oxidative stress in testis and epididymis under IHH. This protection by AA of the IHH-induced lipid peroxidation can be explained in part by the preservation of glutathione reductase activity in these organs.

Melatonin protects the heart, lungs and kidneys from oxidative stress under intermittent hypobaric hypoxia in rats.

Melatonin (N-acetyl-5-methoxytryptamine) is the main secretory product of the pineal gland in all mammals including humans, but it is also produced in other organs. It has been previously demonstrated to be a powerful organ-protective substance under oxidative stress conditions. The aim of this study was to evaluate the protective effect of melatonin in several organs such as heart, lung, kidney, and of the reproductive system, such as testis and epididymis in animals exposed to intermittent hypobaric hypoxia and therefore exposed to oxidative stress and analyzed by lipid peroxidation. Ten-week-old male Wistar rats were divided into 6 groups for 96 hours during 32 days under: 1) Normobaric conditions, 2) plus physiologic solution, 3) plus melatonin, 4) intermittent hypobaric hypoxia, 5 plus physiologic solution and 6) plus melatonin. The animals were injected with melatonin (10 mg/kg body weight) at an interval of 96 hours during 32 days. Results indicated that melatonin decreased lipid peroxidation in heart, kidneys and lung under intermittent hypobaric hypoxia conditions. However, it did not exhibit any protective effect in liver, testis, epididymis and sperm count.

Applications of recombinant Pichia pastoris in the healthcare industry

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.

Acclimatization to chronic intermittent hypoxia in mine workers: a challenge to mountain medicine in Chile

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 (PO₂). 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 effective in offsetting the reduced availability of oxygen at high altitudes. The aims of this review are to summarize findings of the physiological responses to CIH exposure, highlighting outstanding issues in the field.

Blueberry Extracts Protect Testis from Hypobaric Hypoxia Induced Oxidative Stress in Rats

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.

Antioxidant Therapeutic Strategies for Cardiovascular Conditions Associated with Oxidative Stress

Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidant systems, where ROS overwhelms the antioxidant capacity. Excessive presence of ROS results in irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases related to hypoxia, cardiotoxicity and ischemia–reperfusion. Here, we describe the participation of OS in the pathophysiology of cardiovascular conditions such as myocardial infarction, anthracycline cardiotoxicity and congenital heart disease. This review focuses on the different clinical events where redox factors and OS are related to cardiovascular pathophysiology, giving to support for novel pharmacological therapies such as omega 3 fatty acids, non-selective betablockers and microRNAs.

Bacterial consortium for copper extraction from sulphide ore consisting mainly of chalcopyrite

The mining industry is looking forward for bacterial consortia for economic extraction of copper from low-grade ores. The main objective was to determine an optimal bacterial consortium from several bacterial strains to obtain copper from the leach of chalcopyrite. The major native bacterial species involved in the bioleaching of sulphide ore (Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans, Leptospirillum ferrooxidans and Leptospirillum ferriphilum) were isolated and the assays were performed with individual bacteria and in combination with At. thiooxidans. In conclusion, it was found that the consortium integrated by At. ferrooxidans and At. thiooxidans removed 70% of copper in 35 days from the selected ore, showing significant differences with the other consortia, which removed only 35% of copper in 35 days. To validate the assays was done an escalation in columns, where the bacterial consortium achieved a higher percentage of copper extraction regarding to control.

Molecular aspects of breast cancer resistance to drugs (Review)

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.