Respiratory moisture loss and possible pathways of its regulation

Examination of healthy men and those suffering from nonspecific pulmonary diseases has shown that respiratory moisture loss is induced by situation and While "lifting" examinees in the altitude chamber 5000 m upwards intensity of the moisture loss increases to 158%. Essential individual variations of the response are shown. Pulmonary diseases (chronic bronchitis, pneumonia, lecithin synthesis disturbances) make the moisture loss higher. It is concluded that lung surfactants participate in regulation of the respiratory moisture loss. participate in regulation of the respiratory moisture loss.     

Respiratory Intensive Care: A 10-Year Survey

The work of the respiratory intensive care unit at the Glasgow Royal Infirmary covering a period of 10 years and involving more than 2,000 patients has been analysed. The rate of admission of patients with acute respiratory or metabolic disturbances remained surprisingly constant over the years, allowing for the increase in available beds after 1965. A disturbing feature was the notable increase in the incidence of severe self-poisonings. The continued importance of infection as a life-threatening complication is also emphasized. The reduction in mortality observed in some of the most gravely ill patients appears to justify this approach to patient care.     

Conserved signaling pathways genetically associated with longevity across the species

Advanced age is an independent risk factor for natural death and common diseases, such as cardiovascular diseases, dementia, and cancers, which are life-threatening and cause disabilities. On the other hand, individual with healthy longevity is a plausible model for successful aging. Thus, search for longevity-associated genes and pathways likely provides a unique approach to understand the genetic mechanisms underlying aging and healthspan, and emerging evidence from model organisms has highlighted the significance of genetic components in longevity. Here we reviewed the uses of model organisms including yeast, ciliate, nematode, arthropod, fish, rodent, and primate as well as human to identify the genetic determinants of longevity and discussed the genetic contributions of conserved longevity pathways, such as adrenergic system, AMPK, insulin/IGF-1, and mTOR signaling pathways.     

Cardio-Respiratory Coordination Increases during Sleep Apnea

Cardiovascular diseases are the main source of morbidity and mortality in the United States with costs of more than $170 billion. Repetitive respiratory disorders during sleep are assumed to be a major cause of these diseases. Therefore, the understanding of the cardio-respiratory regulation during these events is of high public interest. One of the governing mechanisms is the mutual influence of the cardiac and respiratory oscillations on their respective onsets, the cardio-respiratory coordination (CRC). We analyze this mechanism based on nocturnal measurements of 27 males suffering from obstructive sleep apnea syndrome. Here we find, by using an advanced analysis technique, the coordigram, not only that the occurrence of CRC is significantly more frequent during respiratory sleep disturbances than in normal respiration (p-value<10⁻⁵¹) but also more frequent after these events (p-value<10⁻¹⁵). Especially, the latter finding contradicts the common assumption that spontaneous CRC can only be observed in epochs of relaxed conditions, while our newly discovered epochs of CRC after disturbances are characterized by high autonomic stress. Our findings on the connection between CRC and the appearance of sleep-disordered events require a substantial extension of the current understanding of obstructive sleep apneas and hypopneas.     

Coenzyme Q - Biosynthesis and functions

In addition to its role as a component of the mitochondrial respiratory chain and our only lipid-soluble antioxidant synthesized endogenously, in recent years coenzyme Q (CoQ) has been found to have an increasing number of other important functions required for normal metabolic processes. A number of genetic mutations that reduce CoQ biosynthesis are associated with serious functional disturbances that can be eliminated by dietary administration of this lipid, making CoQ deficiencies the only mitochondrial diseases which can be successfully treated at present. In connection with certain other diseases associated with excessive oxidative stress, the level of CoQ is elevated as a protective response. Aging, certain experimental conditions and several human diseases reduce this level, resulting in serious metabolic disturbances. Since dietary uptake of this lipid is limited, up-regulation of its biosynthetic pathway is of considerable clinical interest. One approach for this purpose is administration of epoxidated all-trans polyisoprenoids, which enhance both CoQ biosynthesis and levels in experimental systems.     

Ribosome-independent biosynthesis of biologically active peptides: Application of synthetic biology to generate structural diversity

Peptide natural products continue to play an important role in modern medicine as last-resort treatments of many life-threatening diseases, as they display many interesting biological activities ranging from antibiotic to antineoplastic. A large fraction of these microbial natural products is assembled by ribosome-independent mechanisms. Progress in sequencing technology and the mechanistic understanding of secondary metabolite pathways has led to the discovery of many formerly cryptic natural products and a molecular understanding of their assembly. Those advances enable us to apply protein and metabolic engineering approaches towards the manipulation of biosynthetic pathways. In this review we discuss the application potential of both templated and non-templated pathways as well as chemoenzymatic strategies for the structural diversification and tailoring of peptide natural products.     

Role of ion channels in heart failure and channelopathies

Heart failure (HF) is a complication of multiple cardiac diseases and is characterized by impaired contractile and electric function. Patients with HF are not only limited by reduced contractile function but are also prone to life-threatening ventricular arrhythmias. HF itself leads to remodeling of ion channels, gap junctions, and intracellular calcium handling abnormalities that in combination with structural remodeling, e.g., fibrosis, produce a substrate for an arrhythmogenic disorders. Not only ventricular life-threatening arrhythmias contribute to increased morbidity and mortality but also atrial arrhythmias, especially atrial fibrillation (AF), are common in HF patients and contribute to morbidity and mortality. The distinct ion channel remodeling processes in HF and in channelopathies associated with HF will be discussed. Further basic research and clinical studies are needed to identify underlying molecular pathways of HF pathophysiology to provide the basis for improved patient care and individualized therapy based on individualized ion channel composition and remodeling.     

Cycloferon efficacy in viral and bacterial diseases of children (clinical review)

The authors' findings and literature data on the pharmacotherapeut efficacy of cycloferon, an interferon inductor (immunomodulators) are described. The drug effect in the treatment of various socially significant children' diseases, including acute respiratory tract viral infection, bronchial asthma, allergic conditions with infection protection disturbances, mycoplasmic infection, bronchopulmonary complications of acute respiratory tract viral infection with low intensity of free radical oxidation is indicated. The use of cycloferon at the background of vaccination was shown to provide inhibition of the autoimmune processes causing postvaccinal complications in frequently ill children. The results of the use of cycloferon in the treatment of gastrointestinal tract and intestinal infections of both the viral and bacterial genesis are discussed. Cycferon is recommended to be used for correction of the intestine dysbiosis (the microflora level came to normal in 95% of the children). The use of the drug in surgical pathology and in particular in appendicular peritonitis for decreasing the postoperative complications and correction of the immune disturbances due to chronic viral hepatitis C and B in children under the complex therapy is described. The cycloferon safety and efficacy were confirmed by the postmarketing randomized trials.     

Integrative analysis of ocular complications in atherosclerosis unveils pathway convergence and crosstalk

Abstract

Atherosclerosis is a life-threatening disease and a major cause of mortalities worldwide. While many of the atherosclerotic sequelae are reflected as microvascular effects in the eye, the molecular mechanisms of their development is not yet known. In this study, we employed a systems biology approach to unveil the most significant events and key molecular mediators of ophthalmic sequelae caused by atherosclerosis. Literature mining was used to identify the proteins involved in both atherosclerosis and ophthalmic diseases. A protein–protein interaction (PPI) network was prepared using the literature-mined seed nodes. Network topological analysis was carried out using Cytoscape, while network nodes were annotated using database for annotation, visualization and integrated discovery in order to identify the most enriched pathways and processes. Network analysis revealed that mitogen-activated protein kinase 1 (MAPK1) and protein kinase C occur with highest betweenness centrality, degree and closeness centrality, thus reflecting their functional importance to the network. Our analysis shows that atherosclerosis-associated ophthalmic complications are caused by the convergence of neurotrophin signaling pathways, multiple immune response pathways and focal adhesion pathway on the MAPK signaling pathway. The PPI network shares features with vasoregression, a process underlying multiple vascular eye diseases. Our study presents a first clear and composite picture of the components and crosstalk of the main pathways of atherosclerosis-induced ocular diseases. The hub bottleneck nodes highlight the presence of molecules important for mediating the ophthalmic complications of atherosclerosis and contain five established drug targets for future therapeutic modulation efforts.     

The role of carbonyl-amine reaction in biological systems and food technology (review of the literature)

Modern ideas about the role of the carbonyl-amine reaction in biochemical systems are reviewed. Some details recently found of the mechanisms of the initial steps of the reactions are considered. The pathways of the formation of numerous by-products are discussed which are very important for taste and aroma of some foodstuffs. Data are presented on nonenzymatic glycosylation of proteins in living organisms, which causes disturbances in their vital functions, diseases and aging. Possible chemical structures of "links" between sugars and protein polypeptide chains, as well as nucleic acids derived from glycosylation are considered. References concerning properties of melanoidins are presented.     

Liver-brain inflammation axis

It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including chronic inflammatory liver diseases, are associated with changes in central neural transmission that result in alterations in behavior. These behavioral changes include sickness behaviors, such as fatigue, cognitive dysfunction, mood disorders, and sleep disturbances. While such behaviors have a significant impact on quality of life, the changes within the brain and the communication pathways between the liver and the brain that give rise to changes in central neural activity are not fully understood. Traditionally, neural and humoral communication pathways have been described, with the three cytokines TNFα, IL-1β, and IL-6 receiving the most attention in mediating communication between the periphery and the brain, in the setting of peripheral inflammation. However, more recently, we described an immune-mediated communication pathway in experimentally induced liver inflammation whereby, in response to activation of resident immune cells in the brain (i.e., the microglia), peripheral circulating monocytes transmigrate into the brain, leading to development of sickness behaviors. These signaling pathways drive changes in behavior by altering central neurotransmitter systems. Specifically, changes in serotonergic and corticotropin-releasing hormone neurotransmission have been demonstrated and implicated in liver inflammation-associated sickness behaviors. Understanding how the liver communicates with the brain in the setting of chronic inflammatory liver diseases will help delineate novel therapeutic targets that can reduce the burden of symptoms in patients with liver disease.     

Spatiotemporal dynamics of regulatory protein recruitment at DNA damage sites

Mammalian cells are constantly threatened by multiple types of DNA lesions arising from various sources like irradiation, environmental agents, replication errors or by-products of the normal cellular metabolism. If not readily detected and repaired these lesions can lead to cell death or to the transformation of cells giving rise to life-threatening diseases like cancer. Multiple specialized repair pathways have evolved to preserve the genetic integrity of a cell. The increasing number of DNA damage sensors, checkpoint regulators, and repair factors identified in the numerous interconnected repair pathways raises the question of how DNA repair is coordinated. In the last decade, various methods have been developed that allow the induction of DNA lesions and subsequent real-time analysis of repair factor assembly at DNA repair sites in living cells. This combination of biophysical and molecular cell biology methods has yielded interesting new insights into the order and kinetics of protein recruitment and identified regulatory sequences and selective loading platforms for the efficient restoration of the genetic and epigenetic integrity of mammalian cells.     

Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates

The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI.     

A novel pathway that regulates inflammatory disease in the respiratory tract

In animals with acute airway inflammation followed by repeated exposure to inhaled Ag, inflammation wanes over time and thus limits the study of chronic airway inflammatory diseases such as asthma. We developed a model of airway inflammation and inhalational exposure to investigate regulatory pathways in the respiratory tract. We show that Th1- and Th2-induced airway inflammation followed by repeated exposure to inhaled Ag leads to a state of immunosuppression. Challenge of these animals with a marked population of TCR transgenic effector Th1 or Th2 cells results in a striking inhibition of inflammation and effector Th cells. In Th2 models, airway hyperresponsiveness, mucus, and eosinophilia are reduced. The inhibitory effects observed are Ag nonspecific, can be induced in lymphocyte-deficient mice, and are associated with a population of TGF-beta1-expressing macrophages. Induction of this pathway may offer potent localized treatment of chronic T cell-mediated respiratory illnesses and provide insights into the development of such diseases.     

Wogonin alleviates liver injury in sepsis through Nrf2-mediated NF-κB signalling suppression

Sepsis is a life-threatening organ dysfunction syndrome, and liver is a susceptible target organ in sepsis, because the activation of inflammatory pathways contributes to septic liver injury. Oxidative stress has been documented to participate in septic liver injury, because it not only directly induces oxidative genotoxicity, but also exacerbates inflammatory pathways to potentiate damage of liver. Therefore, to ameliorate oxidative stress is promising for protecting liver in sepsis. Wogonin is the compound extracted from the medicinal plant Scutellaria baicalensis Geogi and was found to exert therapeutic effects in multiple inflammatory diseases via alleviation of oxidative stress. However, whether wogonin is able to mitigate septic liver injury remains unknown. Herein, we firstly proved that wogonin treatment could improve survival of mice with lipopolysaccharide (LPS)- or caecal ligation and puncture (CLP)-induced sepsis, together with restoration of reduced body temperature and respiratory rate, and suppression of several pro-inflammatory cytokines in circulation. Then, we found that wogonin effectively alleviated liver injury via potentiation of the anti-oxidative capacity. To be specific, wogonin activated Nrf2 thereby promoting expressions of anti-oxidative enzymes including NQO-1, GST, HO-1, SOD1 and SOD2 in hepatocytes. Moreover, wogonin-induced Nrf2 activation could suppress NF-κB-regulated up-regulation of pro-inflammatory cytokines. Ultimately, we provided in vivo evidence that wogonin activated Nrf2 signalling, potentiated anti-oxidative enzymes and inhibited NF-κB-regulated pro-inflammatory signalling. Taken together, this study demonstrates that wogonin can be the potential therapeutic agent for alleviating liver injury in sepsis by simultaneously ameliorating oxidative stress and inflammatory response through the activation of Nrf2.     

Induction of apoptosis in Epstein-Barr virus-infected B-lymphocytes by the NF-kappaB inhibitor DHMEQ

Epstein-Barr virus (EBV) causes EBV-associated lymphoproliferative diseases in patients with profound immune suppression. Most of these diseases are life-threatening and the prognosis of AIDS-associated lymphomas is extremely unfavorable. Polyclonal expansion of virus infected B-cell predisposes them to transformation. We investigated the possibility of nuclear factor kappa B (NF-kappaB) inhibition by dehydroxymethylepoxyquinomicin (DHMEQ) for the treatment and prevention of EBV-associated lymphoproliferative diseases. We examined the effect of DHMEQ on apoptosis induction in four EBV-transformed lymphoblastoid cell lines as well as peripheral blood mononuclear cells infected with EBV under immunosuppressed condition. DHMEQ inhibits NF-kappaB activation in EBV-transformed lymphoblastoid cell lines and induces apoptosis by activation of mitochondrial and membranous pathways. Using an in vivo NOD/SCIDgammac mouse model, we showed that DHMEQ has a potent inhibitory effect on the growth of lymphoblastoid cells. In addition, DHMEQ selectively purges EBV-infected cells expressing latent membrane protein (LMP) 1 from peripheral blood mononuclear cells and inhibits the outgrowth of lymphoblastoid cells. These results suggest that NF-kappaB is a molecular target for the treatment and prevention of EBV-associated lymphoproliferative diseases. As a potent NF-kappaB inhibitor, DHMEQ is a potential compound for applying this strategy in clinical medicine.     

Models and mechanisms of acute lung injury caused by direct insults

Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are life-threatening diseases that are characterized by acute onset, pulmonary inflammation, oedema due to increased vascular permeability and severe hypoxemia. Clinically, ARDS can be divided into ARDS due to direct causes such as pneumonia, aspiration or injurious ventilation, and due to extrapulmonary indirect causes such as sepsis, severe burns or pancreatitis. In order to identify potential therapeutic targets, we asked here whether common molecular mechanisms can be identified that are relevant in different models of the direct form of ALI/ARDS. To this end, we reviewed three widely used models: (a) one based on a biological insult, i.e. instillation of bacterial endotoxins; (b) one based on a chemical insult, i.e. instillation of acid; and (c) one based on a mechanical insult, i.e. injurious ventilation. Studies were included only if the mediator or mechanism of interest was studied in at least two of the three animal models listed above. As endpoints, we selected neutrophil sequestration, permeability, hypoxemia (physiological dysfunction) and survival. Our analysis showed that most studies have focused on mechanisms of pulmonary neutrophil sequestration and models with moderate forms of oedema. The underlying mechanisms that involve canonical inflammatory pathways such as MAP kinases, CXCR2 chemokines, PAF, leukotrienes, adhesions molecules (CD18, ICAM-1) and elastase have been defined relatively well. Further mechanisms including TNF, DARC, HMGB1, PARP, GADD45 and collagenase are under investigation. Such mechanisms that are shared between the three ALI models may represent viable therapeutic targets. However, only few studies have linked these pathways to hypoxemia, the most important clinical aspect of ALI/ARDS. Since moderate oedema does not necessarily lead to hypoxemia, we suggest that the clinical relevance of experimental studies can be further improved by putting greater emphasis on gas exchange.     

Metabolic syndrome and breast cancer: an overview

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the most important cause of cancer-related deaths among women. This disease is on the rise in Turkey. Metabolic syndrome is a cluster of metabolic disturbances including insulin resistance, dyslipidemia, hypertension, abdominal obesity and high blood sugar. Several studies have examined the association of the individual components of the metabolic syndrome with breast cancer. More recent studies have shown it to be an independent risk factor for breast cancer. It has also been associated with poorer prognosis, increased incidence, a more aggressive tumor phenotype. Basic research studies are now in progress to illuminate the molecular pathways and mechanisms that are behind this correlation. Given the fact that all of the components of metabolic syndrome are modifiable risk factors, preventive measures must be established to improve the outcome of breast cancer patients. In this review we set the background by taking into account previous studies which have identified the components of metabolic syndrome individually as breast cancer risk factors. Then we present the latest findings which elaborate possible explanations regarding how metabolic syndrome as a single entity may affect breast cancer risk.     

Recognition of Streptococcus pneumoniae by the innate immune system

Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis. The innate immune system is critical for the control of colonization and for defence during invasive disease. Initially, pneumococci are recognized by different sensors of the innate immune system called pattern recognition receptors (PRRs), which control most subsequent host defence pathways. These PRRs include the transmembrane Toll-like receptors (TLRs) as well as the cytosolic NOD-like receptors (NLRs) and DNA sensors. Recognition of S. pneumoniae by members of these PRR families regulates the production of inflammatory mediators that orchestrate the following immune response of infected as well as neighbouring non-infected cells, stimulates the recruitment of immune cells such as neutrophils and macrophages, and shapes the adaptive immunity. This review summarizes the current knowledge of the function of different PRRs in S. pneumoniae infection.