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North Korea's testing of a nuclear bomb sent out a shock wave throughout the world and totally changed the strategic equation in the Korean peninsula and Northeast Asia. This testing has far-reaching implications for Korean peace and unification, Northeast Asian security and America's global war on terrorism. This key volume provides an in-depth analysis of the inter-Korean and international dynamics of North Korea's nuclear crisis. It offers new insights into the six-party talks designed to resolve the crisis, suggests creative formulas to resolve the ongoing crisis through peaceful, diplomatic means and delves into the interests and policies of the major powers - the US, China, Japan and Russia - at the six-party negotiating table. The contributing authors are distinguished specialists and experts in the field and as such offer valuable expertise into the dynamics of this nuclear crisis for students and academics

A permanent peace regime on the Korean peninsula has yet to be achieved even though the Korean War came to a halt more than half a century ago. Without a peace treaty formally ending the Korean War, the two Korean states are technically still at war. The current situation on the Korean peninsula is extremely tense and precarious, and tensions and distrust between the two Koreas and between the U.S. and North Korea escalated in the wake of North Korea's second underground nuclear weapons testing in 2009. The editors of this volume conceptually present a two-track (inter-Korean and international) approach to Korean peninsula peace-regime building. They argue that an inter-Korean and international approach should be pursued simultaneously for the construction of a permanent peace regime on the Korean peninsula. The contributing authors are established specialists and experts on Korean foreign relations and Northeast Asian international relations. As natives of the U.S., Korea, China, and Japan, they provide objective, scholarly and diverse perspectives on the Korean peace regime building.

Relations between the two Koreas continue to be hostile, volatile and unpredictable with North Korea's nuclear issue remaining as untamed as ever. As such, there is a growing urgency for security cooperation in Northeast Asia to be given immediate attention. The key players in the region - the US, China, Japan and Russia - are keenly aware of the security threat of an armed clash between North and South Korea and are committed to denuclearization of the Korean peninsula. This book explores the domestic factors of the two Koreas and the four major powers that influence their security policies towards North Korea and Northeast Asia. This well thought out and consistently analysed volume has huge potential to frame the conversation on Northeast Asian relations in the coming years.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD+ is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD+ levels by means of NAD(P)H:quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1-/- mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD+/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1-/- mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD+ levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

We previously showed that the matricellular protein CCN5 reverses established cardiac fibrosis (CF) through inducing apoptosis in myofibroblasts (MyoFBs) but not in cardiomyocytes or fibroblasts (FBs). In this study, we set out to elucidate the molecular mechanisms underlying CCN5-mediated selective apoptosis of MyoFBs. We first observed that the apoptotic protein p53 and the anti-apoptotic protein NFκB are simultaneously induced in MyoFBs. When the expression level of p53 was suppressed using a siRNA, CCN5 did not induce apoptosis in MyoFBs. By contrast, when NFκB signaling was inhibited using IKK VII, an IκB inhibitor, MyoFBs underwent apoptosis even in the absence of CCN5. SMAD7 is one of the downstream targets of CCN5 and it was previously shown to potentiate apoptosis in epithelial cells through inhibition of NFκB. In accordance with these reports, when the expression of SMAD7 was suppressed using a siRNA, NFκB signaling was enhanced, and CCN5 did not induce apoptosis. Lastly, we used a luciferase reporter construct to show that CCN5 positively regulated SMAD7 expression at the transcriptional level. Collectively, our data suggest that a delicate balance between the two mutually antagonistic proteins p53 and NFκB is maintained for MyoFBs to survive, and CCN5 tips the balance in favor of the apoptotic protein p53. This study provides insight into the anti-fibrotic activity of CCN5 during the regression of CF.

Human spinal-cord-like tissues induced from human pluripotent stem cells are typically insufficiently mature and do not mimic the morphological features of neurulation. Here, we report a three-dimensional culture system and protocol for the production of human spinal-cord-like organoids (hSCOs) recapitulating the neurulation-like tube-forming morphogenesis of the early spinal cord. The hSCOs exhibited neurulation-like tube-forming morphogenesis, cellular differentiation into the major types of spinal-cord neurons as well as glial cells, and mature synaptic functional activities, among other features of the development of the spinal cord. We used the hSCOs to screen for antiepileptic drugs that can cause neural-tube defects. hSCOs may also facilitate the study of the development of the human spinal cord and the modelling of diseases associated with neural-tube defects. A protocol for the production of human spinal-cord-like organoids that recapitulate the tube-forming morphogenesis of the early human spinal cord facilitates screening for antiepileptic drugs that can cause neural-tube defects.

Obesity is associated with various human disorders, such as type 2 diabetes, cardiovascular diseases, hypertension, and cancers. In this study, we observed that knockout (KO) of CCN5, which encodes a matricellular protein, caused mild obesity in mice. The CCN5 KO mice also exhibited mild diabetes characterized by high fasting glucose levels and impaired insulin and glucose tolerances. Cardiac hypertrophy, ectopic lipid accumulation, and impaired lipid metabolism in hearts were observed in the CCN5 KO mice, as determined using histology, quantitative RT-PCR, and western blotting. Fibrosis was significantly greater in hearts from the CCN5 KO mice both in interstitial and perivascular regions, which was accompanied by higher expression of pro-fibrotic and pro-inflammatory genes. Both systolic and diastolic functions were significantly impaired in hearts from the CCN5 KO mice, as assessed using echocardiography. Taken together, these results indicate that CCN5 KO leads to lipotoxic cardiomyopathy with mild obesity and diabetes in mice.

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.

Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD + ) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD + levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD + levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD + levels and the p53-microRNA-34a pathway in caerulein-induced AP. Moreover, we confirmed that the increase of cellular NAD + by NQO1 enzymatic action using the substrate β-Lapachone suppressed caerulein-induced AP with down-regulating TLR4-mediated inflammasome signalling, and thereby reducing the inflammatory responses and pancreatic cell death. These results suggest that pharmacological stimulation of NQO1 could be a promising therapeutic strategy to protect against pathological tissue damage in AP.

NADH-quinone oxidoreductase 1 (NQO1) modulates cellular NAD(+)/NADH ratio which has been associated with the aging and anti-aging mechanisms of calorie restriction (CR). Here, we demonstrate that the facilitation of NQO1 activity by feeding β-lapachone (βL), an exogenous NQO1 co-substrate, prevented age-dependent decline of motor and cognitive function in aged mice. βL-fed mice did not alter their food-intake or locomotor activity but did increase their energy expenditure as measured by oxygen consumption and heat generation. Mitochondrial structure and numbers were disorganized and decreased in the muscles of control diet group but those defects were less severe in βL-fed aged mice. Furthermore, for a subset of genes associated with energy metabolism, mice fed the βL-diet showed similar changes in gene expression to the CR group (fed 70% of the control diet). These results support the potentiation of NQO1 activity by a βL diet and could be an option for preventing age-related decline of muscle and brain functions.