Cyytoprotective Role Of DJ-1, Mitophagy And Cell Death

Emphysema is the most common cause of death from respiratory disease in the United States and is generally caused by several years of heavy cigarette smoking (Olendorf, 2000). When a person smokes, the body’s immune system tries to fight off the invading smoke by using certain substances. These substances can also attack the cells of the lungs, but normally the body is able to release other substances to prevent this. In the case of people who are smokers, this doesn’t happen and the original substances that were released to fight off the smoke also end up injuring the cells of the lungs as well. Eventually, the lungs will not be able to supply enough oxygen to the blood and a host of problems can occur with this. Risk factors that have been identified for emphysema include exposure to tobacco smoke either through active or passive smoking (2nd hand smoke), occupational exposure such as dust or chemicals, ambient air pollution, or genetic abnormalities, including a deficiency of alpha-antitrypsin, an enzyme inhibitor that normally counteracts the destruction of lung tissue by certain other enzymes (Smeltzer, 2010). The symptoms of emphysema develop gradually over many years. It is generally characterized by three primary symptoms: chronic cough, sputum production, and dyspnea on exertion. Other signs and symptoms include weight loss and the development of a

My Dad recently passed away unannounced though advanced in age. I think if I had an in depth knowledge of what took him away so quick, I would have been able to convince and or lure him out of such sudden departure. He had been a chronic smoker for a short period of time. He might have suffered a lot I believe; with inference from the kind of disease the autopsy result diagnosed him of Emphysema, as the major causative factor to his unannounced departure. I am leading this discussion with research into the disease Emphysema to gain more knowledge to help many I know that smoke a lot most especially, the would be ardent smokers so that they do not go through what my father went through, suffered and consequently leaving us into social and paternal vacuum of life. I would like us look into what is emphysema? Followed by how it affects the lung,

Emphysema is the third leading cause of death in the United States. It is a chronic, progressive disease that affects the morbidity and mortality of life. Like many chronic diseases, diagnosis is affected by numerous variables. There is no cure; however, there are effective treatment methods which can slow the progression of the disease and allow for a normal life. In short, the diagnosis of emphysema is not a death sentence. Rather, it is an illness that should prompt a person diagnosed with it to take the lead in the management of the disease. The primary risk factor for this disease that can be controlled is the smoking of cigarettes. Smoking cessation is the most beneficial first step to preventing or stopping the development or progression

Emphysema is a condition of the lungs that involves the over-inflation of the air sacs, otherwise known as the alveoli. Normal functioning of the alveoli helps breathing in normal respiration. Unlike other lung diseases this one can be inherited. This is a disease that can affect people of all ages and genders. In 1994, the number of males with emphysema outnumbered the females by fifty four percent. However, in the two years that followed the difference between males and females decreased by ten percent.

The importance of these cells as targets in lung regeneration is supported by a recent publication on transplantation of ATII cells obtained from control organ donors to the lung of patients with IPF (4). This suggests that therapeutic targeting ATII cell proliferation and transdifferentiation to alveolar type I cells may induce lung regeneration in IPF.

Cigarette smoke induces oxidative stress, which may lead to lung injury and emphysema development. We found high mitochondrial DNA damage in alveolar type II cells isolated from individuals with this disease. We have discovered that XLF is involved in repair of mitochondrial DNA in these cells. XLF oxidation causes its degradation leading to mitochondrial dysfunction and mitophagy in these cells. Targeting XLF may provide potential therapeutic strategy against emphysema

Allergic Asthma is an inflammatory disease of the lungs that is characterized by increased infiltration of leukocytes, into the airways and limits respiratory function. The studies suggest that a defective general regulatory system against inflammation could be a significant factor in allergic asthma. Mesenchymal stem cells have potential as a cellular immunosuppressive therapy for inflammatory disorders. We investigated whether administration of Mesenchymal stem cells during allergen challenge would affect the underlying mechanisms in allergic airways inflammation. Mice were sensitized by intraperitoneal injection of ovalbumin and aluminum hydroxide emulsion on days 0, 7 and 14 and were then challenged intranasally with ovalbumin or sterile

Alveolar type II (ATII) cells have a highly oxidative phenotype and numerous mitochondria (1). They are heavily dependent on mitochondrial function for energy generation required for pulmonary surfactant production, fluid transport and transdifferentation to alveolar type I cells to restore the epithelium after damage (2, 3). Cigarette smoking (CS) induces oxidative stress and is one of the most common causes of ATII cell injury and pulmonary emphysema. DJ-1 serves as a sensor of redox status and protect cells from oxidative stress (4). It is localized in the mitochondria, cytoplasm and nucleus. The oxidation of cysteine at position 106 (Cys106) to a sulfinate enhances DJ-1’s cytoprotective activity. We found further oxidized DJ-1 to

Emphysema is a disease which specifically targets the alveoli, or air sacs. According to the Cleveland Clinic, “there are about three hundreds million alveoli in normal lungs.”[3] The alveoli are very necessary for the body because they suck the oxygen from air and rid carbon dioxide out of the body, and they important for connections between the respiratory system and circulatory system, or blood vessels. In emphysema, the alveoli more gradually damaged and rupture. Additionally, the weakness the inner wall of alveoli, which made one larger air space rather of many tiny ones. As a result, the alveoli can not shrink and expand probably as usual. Moreover, this damage leads to reduced the surface of the lungs. Therefore, the amount of oxygen

We already isolated ATII cells from human lung and cultured them using methods previously described in the literature (7). We can also transdifferentiate ATII cells to alveolar type I cells (Fig. 2). We found decreased ability of ATII cells isolated from IPF patients to transdifferentiate to alveolar type I cells compared to controls. To our knowledge, this experiment has not been performed using ATII cells obtained from individuals with IPF or other lung diseases. Moreover, we also observed lower levels of aquaporin 5, which is a marker of alveolar type I cells (Fig. 2). These preliminary data indicate the feasibility of proposed experiments in this application. Our results suggest the impaired ability of ATII cells to transdifferentiate to alveolar type I cells in IPF.

In addition, a novel immunocytochemistry protocol was optimized in order to determine co-localization of BRCAs and mitochondria in LCLs. Lymphoblastoid cell lines were used because it was reported to have the highest relative expression of endogenous LRRK2 in the myeloid lineage37. Investigating the changes in the expression of DNA repair proteins would allow for a better understanding of the role DNA repair pathways play in mtDNA damage within the context of LRRK2 G2019S mutation. As LRRK2 function is understood as a multi-functional gene that influences many different organelles, understanding the correlation between LRRK2 and DNA repair pathway signaling may open up another avenue to better understand the normal function of LRRK2 as well as in PD. Furthermore, assessment of these proteins may also lead to new therapeutic

Dr. Kosmider has publications with Dr. Steven Kelsen, who is a co-investigator on this grant. His clinical and research interests are focused on signaling pathways and the pathophysiology of oxidant stress-induced epithelial injury. He has training in respiratory medicine and physiology and will provide knowledge of the lung diseases. He has also collaborated with Dr. Muniswamy Madesh, a co-investigator in this project, who is an expert in studies of mitochondrial dysfunction and mechanisms of mitochondrial induced apoptosis.

Mitochondrial fission requires dynamin-related protein 1 (Drp1). Drp1 is a large GTPase that can assemble into oligomers with enhanced GTPase activity. Drp1 is predominantly located in the cytosol and can be recruited to mitochondria to mediate mitochondrial fission by forming an oligomeric ring around the mitochondrial tubule to constrict and sever mitochondrial outer membranes 38-43. Having found that dysbindin-1 regulates mitochondrial fission, we proceeded to test whether dysbindin-1 is involved in the association of Drp1 with mitochondria. Cultured hippocampal neurons (DIV14) were transfected with the mitoDsRed plasmid along with the dysbindin-1 siRNAs, scrambled siRNAs, dysbindin-1C or -1A

SelW expression it has been found to work as regulated during C2C12 cell differentiation (Noh et al 2010). The mRNA level of SelW through the differentiation process of myoblasts and the optimal Se concentrations for expression of SelW mRNA in chicken myoblasts is 10−7 M is influenced by Se( Ruan et al 2012.) Overexpression of SEPW could decrease the H2O2- influence oxidative damage.furthermore, the increased expression of certain antioxidative selenoproteins could regulate oxidation–reduction homeostasis in cells, improve the ability of cells to save against oxidative stress and reduce the oxidative damage and the concentration of H2O2 (Yao et al 2014). overexpression of SelW experiment indicated that it might play important role in component of the cellular defense system against oxidative stress (Sun et al., 2001) . Increased of Malondialdehyde (MDA) levels found to be induced with SEPW1 deficiency , also It is reported that Sepw1 deficiency reduced the ability of myoblasts to buffer the exogenous H2O2 and increased the sensitivity of cells to H2O2. Therefore, Sepw1 plays beneficial role in antioxidative functions in myoblasts also indicating that Sepw1 and Gpx1 may play important roles in the response to oxidative stress in chicken myoblasts. Therefore, chicken Sepw1 also preserves antioxidative function (Yao et al 2014).

Innovation: Studies of alveolar type II (ATII) cell-derived exosomes obtained from bronchoalveolar lavage fluid (BALF) and blood obtained from patients with lung transplant (LT) are novel. Analysis of their harmful content and autocrine effects represents a new paradigm for understanding LT rejection. Our Preliminary Results indicate the presence of a membrane surfactant protein C (SP-C) in exosomes isolated from BALF and blood (data not shown), which indicates their ATII cell origin. Our proposal is innovative in several ways: