A mitochondrial superoxide theory for oxidative stress diseases and aging

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O₂^•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q₁₀) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.     

Case of primary pulmonary cryptococcosis accompanied by severe back pain]

We report a case of primary pulmonary cryptococcosis. A 43-year-old male, without any significant underlying disease or immunological abnormalities, was admitted to our hospital with a complaint of sudden onset of severe back pain. His chest-X-ray and computed tomography revealed infiltrative shadows in the left lower lung without any signs of pleural effusion. Through transbronchial biopsy, cryptococcosis was obtained. Cryptococcal antigen also tested positive, we diagnosed this case as primary pulmonary cryptococcosis. And started anti-fungal therapy (fluconazole) consisting of parenteral and oral fluconazole. As soon as anti-fungal therapy was started, both the chest X-ray findings and cryptococcal antigen showed general improvement. Furthermore, subjective symptoms subsided immediately after treatment, During follow up through the outpatient clinic, his symptomatic complaint and chest roentgenogram shows improvements. This case was noteworthy for two reasons: 1) In cases with chest X-rays showing infiltrative shadows but lacking any underlying diseases, pulmonary cryptococcosis should be considered. 2) Sudden onset of back pain is a rare but a possible primary symptom of pulmonary cryptococcosis.     

Lnk prevents inflammatory CD8+ T‐cell proliferation and contributes to intestinal homeostasis

The intracellular adaptor Lnk (also known as SH2B3) regulates cytokine signals that control lymphohematopoiesis, and Lnk^?/? mice have expanded B‐cell, megakaryocyte, and hematopoietic stem‐cell populations. Moreover, mutations in the LNK gene are found in patients with myeloproliferative disease, whereas LNK polymorphisms have recently been associated with inflammatory and autoimmune diseases, including celiac disease. Here, we describe a previously unrecognized function of Lnk in the control of inflammatory CD8⁺ T‐cell proliferation and in intestinal homeostasis. Mature T cells from newly generated Lnk–Venus reporter mice had low but substantial expression of Lnk, whereas Lnk expression was downregulated during homeostatic T‐cell proliferation under lymphopenic conditions. The numbers of CD44^hiIFN‐γ⁺CD8⁺ effector or memory T cells were found to be increased in Lnk^?/? mice, which also exhibited shortening of villi in the small intestine. Lnk^?/? CD8⁺ T cells survived longer in response to stimulation with IL‐15 and proliferated even in nonlymphopenic hosts. Transfer of Lnk^?/? CD8⁺ T cells together with WT CD4⁺ T cells into Rag2‐deficient mice recapitulated a sign of villous abnormality. Our results reveal a link between Lnk and immune cell‐mediated intestinal tissue destruction.     

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

Infiltrating macrophages accumulate in fatty streak lesions and transform into foam cells, leading to the formation of atherosclerotic plaques. Inflammatory mechanisms underlying the plaque formation mediated by NKG2D-positive lymphocytes such as CD8⁺ T cells, natural killer cells and natural killer T cells have been extensively investigated. Yet, the involvement of the NKG2D system itself remains poorly understood. Recent work in mouse models has shown that blockade of an NKG2D receptor–ligand interaction reduces plaque formation and suppresses inflammation in aortae. In this study, we conducted immunohistochemical analysis of NKG2D ligand expression in autopsy-derived aortic specimens. Foam cells expressing NKG2D ligands MICA/B were found in advanced atherosclerotic lesions accompanied by a large necrotic core or hemorrhage. Human monocyte-derived macrophages treated in vitro with acetylated low-density lipoproteins enhanced expression of MICA/B and scavenger receptor A, thus accounting for NKG2D ligand expression in foam cells infiltrating atherosclerotic plaques. Our results suggest that, as in mice, the NKG2D system might be involved in the development of atherosclerosis in humans.