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Nicotinamide adenine dinucleotide(NAD') is a classic coenzyme playing a critical role in cellular redox reactions. Emerging evidence demonstrates that NAD' and its key mediators, NAD+-dependent protein deacetylases (sirtuins), together regulate many important meta- bolic pathways including mitochondrial function. Thus, impaired NAD' biosynthesis is critically involved in the pathophysiology of aging and age-associated diseases. Importantly, administration of key NAD+ intermediates, such as nicotinamide mononucleotide(NMN) or nicotinamide riboside (NR), improves mitochondrial function and exerts remarkable therapeutic effects for various age-associated diseases, such as diabetes and cancer, in mice. In this review, we will summarize and discuss pathophysiological relevance and translational potential of NAD' biology and mitochondrial sirtuin(SIRT3) in age-associated diseases.

Paraneoplastic neurological syndromes (PNSs) are the remote effects of cancer on the nervous system. The peripheral nervous system is an important targets of PNS. The neuropathies associated with PNS are reviewed in this article. Among the various paraneoplastic neuropathies, the main classical syndorome of PNS is subacute sensory neuronopathy that involves the cell bodies of sensory neurons in the dorsal root ganglia. Its clinical symptoms include sensory ataxia. Onconeuronal antibodies such as anti-Hu and anti-CV2/CRMP5 antibodies are frequently associated with this syndrome. In contrast to this classical form of PNS, non-classical syndromes are considered as heterogeneous neuropathies. The clinical features of non-classical syndromes are variable and no evident association between a clinical phenotype and onconeuronal antibodies has been established. Early detection and treatment of cancer is an essential for management of PNS. Neuropathies with paraproteinemia are also important clinical entities of PNS. IgM M-protein is most likely to cause neuropathy. Patients with IgM paraproteinemic neuropathy is usually characterized by predominan distal and sensory impairment, prolonged distal motor latencies in nerve conduction studies, and the presence of anti-MAG and SGPG antibodies.

Limbic encephalitis is a paraneoplastic syndrome that is often associated with small cell lung cancer (SCLC), breast cancer, testicular tumors, teratoma, Hodgkin's lymphoma and thymoma. The common clinical manifestations of limbic encephalitis are subacute onset, cognitive dysfunction, seizures and psychiatric symptoms. Paraneoplastic neurological disorders are considered to occur because of cytotoxic T cell responses and antibodies against target neuronal proteins that are usually expressed by an underlying tumor. The main intracellular antigens related to limbic encephalitis are Hu, Ma2, and less frequently CV2/CRMP5 and amphiphysin. The anti-Hu antibody, which is involved in cerebellar degeneration and extensive or multifocal encephalomyelitis such as limbic encephalitis is closely associated with a history of smoking and SCLC. The anti-Ma2 antibody is associated with encephalitis of the limbic system, hypothalamus and brain-stem. For this reason, some patients with limbic encephalitis have sleep disorders (including REM sleep abnormalities), severe hypokinesis and gaze palsy in addition to limbic dysfunction. In men aged less than 50 years, anti-Ma2 antibody encephalitis is almost always associated with testicular germ-cell tumors that are occasionally difficult to detect. In older men and women, the most common tumors are non-SCLC and breast cancer. Limbic encephalitis associated with cell-surface antigens (e.g., voltage-gated potassium channels, NMDA receptors) is mediated by antibodies and often improves after a reduction in the antibody titer and after tumor resection. Patients with antibodies against intracellular antigens, except for those with anti-Ma2 antibodies and testicular tumors, are less responsive. Early diagnosis and treatment with immunotherapy, tumor resection or both are important for improving or stabilizing the condition of limbic encephalitis.

Paraneoplastic retinopathy including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), and paraneoplastic optic neuropathy (PON) are visual disorders associated with systemic cancer. Patients with CAR typically present with progressive loss of vision and photopsia, which are related to dysfunction of both cones and rods in photoreceptors. The triad of photosensitivity, ring scotoma, and a reduced caliber of the retinal arteriole along with undetectable signals in electroretinogram (ERG) are specific manifestations of CAR. CAR is associated most commonly with small-cell lung cancer (SCLC) and occasionally with gynecologic tumors, and it is usually caused by autoantibodies against recovering, which is a calcium-binding photoreceptor protein that participates in the transduction of light. MAR is characterized by shimmering, flickering, or pulsating photopsias, and usually occurs in the patients with a cutaneous melanoma. MAR differs from CAR in terms of visual acuity and color vision and is associated with a characteristic pattern detected in ERG. Autoantibodies against the bipolar cells of the retina have been identified in patients with MAR. Patients with PON frequently present with progressive visual loss and optic disc edema, or with other paneoplastic neurologic syndromes related to SCLC, such as paraneoplastic encephalomyelitis or retinitis, ophthalmoplegia, and subacute cerebellar syndrome. Autoantibodies against collapsin-responsive mediator protein-5 (CRMP-5, also called anti-CV2) are considered to be as the causative factor. Treatments with corticosteroids, plasma exchange, and intravenous immune globulin as well as treatment of the tumor itself, occasionally improves these paraneoplastic visual syndromes. However, the prognosis depends on their underlying malignancy.

Rheumatoid arthritis is a chronic inflammatory polyarthritis and is thought to be an autoimmune, multifactorial and polygenic disease. Recent studies have uncovered many important players in the pathogenesis of rheumatoid arthritis. Immune cells, mesenchymal cells, and bone-associated cells are all involved in the pathogenesis and are closely related with each other. The genetic predisposition to rheumatoid arthritis is confirmed by many family studies and HLA association studies. Genome-wide disease association studies identified genetic risk foci, such as HLA-DRB1, PADI4, and PTPN22. In addition to the genetic contribution, environmental factors are increasingly recognized. Many studies revealed that smoking is a risk factor for rheumatoid arthritis. The role of B and T lymphocytes in the pathogenesis has been reevaluated by biological agents such as rituximab (anti-CD20 antibody) and abatacept (CTLA4-Ig) , respectively. T cells in rheumatoid arthritis have been shown to have the altered level of surface molecules such as CD28, cytokine pattern shift, and shortened telomere lengths. Moreover, telomere loss is recognized not only in lymphocytes but also in hematopoietic progenitor cells. This phenomenon and the presence of rheumatoid-specific anti-citrullinated protein antibodies are reported to be associated with HLA haplotypes.

Limbic encephalitis refers to an inflammatory process involving the hippocampi. amygdala and less frequently frontobasal and insular regions. This disorder used to be considered extremely rare, invariably associated with cancer, and unresponsive to treatment. However, recent studies suggest that limbic encephalitis is more frequent than it was previously thought, and a substantial number of patients may recover. This is due in part to the development of clinical diagnostic criteria and identification of antibodies directed against two broad categories of antigens: (1) intracellular or classical paraneoplastic antigens, including Hu, Ma2, and CV2 CRMP5, among others, and (2) cell surface antigens including, voltage-gated potassium channels (VGKC), N-methyl-D-aspartate receptor (NMDAR), and others expressed in the neuropil of the hippocampus. While the disorders related to the first category of antibodies associate with cancer (lung, testis and other), prominent brain infiltrates of T-cells, and limited response to treatment, the disorders related to the second category of antibodies associate with other tumors (thymoma. teratoma, Hodgkin's lymphoma), appear to be antibody-mediated, and respond better to immunotherapy. Of particular interest in the later group is the disorder that associates with antibodies to extracellular epitopes of NR1/NR2 heteromers of the NMDA receptor. Patients with this syndrome may present as limbic encephalitis but more frequently manifest severe psychiatric symptoms, seizures, dyskinesias, autonomic instability or hypoventilation. In all, the study of these disorders provides a link between immunologic processes and neuronal events involved in memory, cognition, seizures, and neuronal degeneration.

The recent methodological advances in molecular biology, immunology, and genetics have clarified neuroimmunological problems in axonal Guillain-Barré syndrome, seronegative myasthenia gravis, paraneoplastic neurologic syndromes and many others. In addition to clinical and serological studies in peripheral neuropathies, the origins and measurement of anti-ganglioside antibodies and relationships to similar carbohydrate structures on infectious organisms are discussed in the context of molecular mimicry hypothesis, especially related with both the localization of relevant gangliosides in the nerve and clinical phenotypes. Major advances have been made in animal modeling of anti-ganglioside antibody-associated disease. An explanation for muscular weakness in 10-15% of patients with seronegative myasthenia gravis who lack autoantibodies to acetylcholine receptors(AchRs) appears to be the autoantibodies to muscle-specific receptor tyrosine kinase (MuSK). MuSK mediates agrin-induced clustering of AchRs during synapse formation. These autoantibodies to the extracellular domain of MuSK inhibit its function in tissue culture. Isoelectric focusing (IEF) and agar gel electrophoresis (AGE) are used to examine cerebrospinal fluid (CSF) and sera from patients with multiple sclerosis (MS). The CSF oligoclonal IgG bands (OB) are less frequently observed in Japanese MS patients compared with Caucasian patients. Few optic-spinal form of MS (OS-MS) was positive for OB by agarose gel electrophoresis, but IEF is more sensitive than AGE. Recent IEF data revealed some OS-MS patients were positive for OB. The neuroimmunological advances revealed the relationship between the neuroimmunological diseases and the putative autoantibodies as diagnostic markers, for example, HAM and hnRNP-A1, MSand anti-hnRNP-B1 antibody, opsoclonus-myoclonus syndrome and anti-GluRdelta2 antibody, Rasmussen encephalitis and anti-GluR3 antibody, paraneoplastic brainstem encephalitis and anti-Ma2 antibody, and so on.

Enzymes proceed the reaction with high regio- and stereoselectivity under mild conditions, i.e. in an aqueous medium at room temperature. However, enzymatic reactions that catalyze carbon-carbon bond formation have not been utilized in organic synthesis until recently. We had an interest in an aldolase-catalyzed reaction which proceed carbon-carbon bond formation referred to aldol condensation, by which many bioactive compounds have been rationally synthesized. On the other hand, recent biological studies on cell recognition (cell adhesion) have disclosed the important roles of oligosaccharides on cell surfaces, especially which include glucuronic acid, 3-deoxy-D-manno-oct-2-ulosonic acid (KDO), and sialic acid in the structures e.g., sialyl Lewis X and endotoxins, in differentiation, induction, viral and bacterial infections, and immune response. As well as acidic oligosaccharides, basic ones have been utilized as practical medicines in the clinical level, like acarbose that acts as an amylase inhibitor. Based on these background, we embarked the synthesis of carbohydrate related compounds which can control the interaction between carbohydrates and carbohydrate recognition protein by the use of several aldolases. Azasugars, potent inhibitors toward glycosidases, were synthesized using fructose-1,6-diphosphate (FDP)-aldolase and other dihdroxyacetonephosphate (DHAP)-dependent aldolases in the key step. Sialyl Lewis X mimetic, peptidic mimetic of RNA having anti-Vero toxin activity, mycestericin D, and aza-idulonic acid were prepared by taking advantage of L-threonine aldolase catalyzed reaction, which afford beta-hydroxy-alpha-L-amino acids. A precursor of KDO, featured acidic sugar of endotoxins was provided by the reaction catalyzed with kynureninase, which generates beta-anion of L-alanine in its active site during the metabolic reaction from kynurenine to anthranilic acid.