The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Aims: Alterations in calcium homeostasis in the intracellular endo/sarcoplasmic reticulum (ER/SR) and mitochondria of cardiomyocytes cause cell death via the SR a

/pdf/role-of-the-calcium-sensing-receptor-in-cardiomyocyte-4ctcm3kqf6.pdf

Role of the Calcium-Sensing Receptor in Cardiomyocyte Apoptosis via the Sarcoplasmic Reticulum and Mitochondrial Death Pathway in Cardiac Hypertrophy and Heart Failure

https://www.cell.com/cell/pdf/S0092-8674(05)00109-1.pdf

Mitochondria, Oxidants, and Aging

Beckman, Kenneth B., and Bruce N. Ames. The Free Radical Theory of Aging Matures. Physiol. Rev. 78: 547–581, 1998. — The free radical theory of aging, conceived in 1956, has turned 40 and is rapidl...

/pdf/the-free-radical-theory-of-aging-matures-3b861ahk8h.pdf

The Free Radical Theory of Aging Matures

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

血中LDLコレステロール値測定にはFriedewaldの式による計算法に対し, 近年直接測定する方法 (直接法) が開発されたがその普及率はいまだ高くない。また, 健診前夜の夕食の種類による血清脂質濃度変化の詳細な検討はない。そこで直接法の有用性および前夜摂取した夕食による変動を検討した。健康な男女35人に全員同時に3回の試験を行った。第1回目の試験は午後7時に被検者全員が同一の普通食 (658 kcal) を摂取し以後は禁食とした。翌朝午前8時に採血を行い糖質と脂質濃度を測定した。LDL-コレステロール値は直接法と計算法とで求めた。1週後に第2回目として夕食に高エネルギー食 (普通食に比し糖質のみを増量したもの, 1, 011 kcal) を用い, 次の1週後に第3回目として夕食を絶食とし, 1回目と同様に8時に採血し糖質と脂質濃度を測定した。中性脂肪値, 総コレステロール値およびHDL-コレステロール値は3種の食餌問に有意差はみられなかったが, グルコース値は, 絶食 (84.4±8.6mg/dl) で普通食 (87.1±7.4mg/dl) , 高エネルギー食 (87.2±8.4mg/dl) に比べて有意な低下が見られた。LDL-コレステロール値 (直接法) は, 普通食に比べ高エネルギー食 (101.5±22.1, 104.3±24.1mg/dl) で高い傾向を示し, 絶食で有意な上昇がみられた (105.5±23.3mg/dl) 。しかし計算法値では, 絶食での有意な上昇は検出されず, 高エネルギー食 (99.7±24.7mg/dl) では逆に普通食 (105.1±23.9mg/dl) および絶食 (108.7±26.0mg/dl) よりも有意に低下する結果となった。また, 普通食および絶食では直接法値よりも計算法値が高くなる人が多かったのに対し, 高エネルギー食では逆に計算法値が低くなる人が多かった。以上より, 健診においてはLDL-コレステロール測定を直接法へ迅速に移行することが必要であり, 前日の夕食については標準的カロリーの食事を勧める記載が必要と考えられた。

Cautions in Evaluation of Serum LDL-cholesterol

Reactive oxygens and nitric oxide

The hypotheses that nitrotyrosine formation is a downstream mechanism following TNF-α production in lipopolysaccharide (LPS)-induced liver injury and its inhibition reduces the injury were examined. Under anesthesia, experiments were performed 6h after the intravenous administration of LPS (10mg/kg) or saline using male Sprague-Dawley rats (300-400g). Liver injury was evaluated in 4 groups: control (n=4), LPS alone (n=5), LPS+quercetin (n=5), LPS+clodronate (n=5) by plasma alanine aminotransferase (ALT) level, nitrotyrosine concentration in liver and histological changes. Quercetin, an inhibitor of nitrotyrosine formation was injected at a dose of 50mg/kg i.p. 24h before the LPS injection and clodronate, a Kupffer cell remover was injected i.v. at a dose of 0.2ml (0.23M) 24h before the LPS injection. Nitrotyrosine was measured by enzyme-linked immunosorbent assay and high performance liquid chromatography-electrochemical detection methods. In the LPS group, the liver contained 1, 403±240ng nitrotyrosine/g protein (control: 21.2±1.7ng/g) and plasma ALT was elevated (1, 781±455IU/liter vs. control 55±5IU/liter). Nitrotyrosine formation was decreased in the LPS+quercetin and LPS+clodronate groups (240.6±47.6 and 301.4±26.2ng/g protein, respectively) and the increase of plasma ALT was attenuated (486±20.7 and 79.8±9.4IU/liter, respectively). The plasma TNF-α level was markedly elevated in the LPS group (1, 124.1±67.6pg/ml). It remained high in quercetin groups (1, 292.4±159.9pg/ml) but was very low in the clodronate group (34.8±5.3pg/ml). LPS-induced liver injury involves nitrotyrosine formation and treatments to decrease its formation attenuated the injury. The protection was observed without affecting TNF-α level; suggesting that the nitrotyrosine formation is a downstream mechanism for the injury following TNF-α production.

https://www.jstage.jst.go.jp/article/jcbn1986/33/2/33_2_61/_pdf

Inhibition of Nitrotyrosine Formation Reduces Endotoxin-Induced Liver Injury Irrespective of TNF-.ALPHA.

Anti-inflammatory effect of Pelteobagrus nudiceps extract on rat model of CFA-induced pulmonary tuberculous granuloma

Ex vivo monitor of superoxide generation by invaded phagocytes in peri-myocarditis

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