Representative remodeling of the kidney in CKD includes development of glomerulosclerosis and tubulointerstitial fibrosis. Injury to glomerular endothelium, mesangium, or podocyte can induce glomerulosclerosis, although recent studies have focused on a role of podocytes due to its lack of proliferation. Development of tubulointerstitial fibrosis is multi-factorial, and includes proteinuria, chronic hypoxia, activation of the intra-renal renin-angiotensin system, imbalance of matrix production and protease activity, and epithelial-mesenchymal transdifferentiation. Optimal remodeling may induce restoration of normal kidney structure, and some potential candidates of resident renal stem cells have been proposed. Development of therapeutic approaches targeting final common pathways will open a new avenue in management of patients with CKD.

In orthodontic treatment, the role of periodontal ligament is essential for the teeth to move within the alveolar process against the mechanical stress. Mesenchymal stem cells that differentiate to chondrocytes, adipocytes, and nerve cells is known to exist in the PDL. In both process of physiological and orthodontic tooth movement, bone resorption mainly occurs at the anterior region toward the direction of tooth movement, and bone apposition/formation at the posterior region to the direction of the tooth movement, and bone turnover occurs locally and site specifically, which results in constant reconstruction of the alveolar process in 3 dimension. Among the bone cells, osteocytes act as a major role in bone remodelling during orthodontic tooth movement against mechanical stress. Moreover, the side effect during tooth movement is known to be the pain and external apical root resorption.

Crow-Fukase syndrome is diagnosed based on the presence of chronic sensori-motor polyneuropathy along with other characteristic generalized symptoms denoted by the acronym of POEMS which stands for polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. In this syndrome, the serum levels of the vascular endothelial growth factor (VEGF) are abnormally elevated, and this is a predictive factor for its diagnosis. Although the causes of CFS/POEMS remain unknown, VEGF is evidently correlated with its pathogenesis. Human glioblastoma cells are known to express VEGF. In models of CFS/POEMS, mice that are peritoneally transplanted with human glioblastomas exhibit high serum levels of VEGF, prominent edema with increased circulation volume, and pathological findings in the liver, spleen, and kidney. VEGF that is highly concentrated in platelets may be released in massive amounts due to coagulation in the peripheral tissue and may thus exert its maximal physiological effects and produce the abovementioned diffuse pathological findings. The correlation between polyneuropathy and elevated VEGF remains unclear. However, VEGF may affect the blood-nerve barrier by increased microvascular hyperpermeability, upregulated cytokines such as matrix metalloproteases may induce blood-nerve barrier breakdown and demyelination of the peripheral nerve. Furthermore, microangiopathy due to proliferative endothelial cells and hypercoagulated occlusion also affect axonal damage. Novel strategies that have recently been proposed for the management of this disease include high-dose chemotherapy combined with autologous peripheral blood stem cell transplantation (PBSCT) and molecular-targeted therapy against plasma cells and VEGF. Notably, PBSCT exerts a dramatic effect on polyneuropathy; such an effect has rarely been achieved by the previously described modalities of low-dose melphallan and steroid therapy. PBSCT is observed to induce a rapid and persistent decrease in the serum VEGF levels. In conclusion, VEGF is not only the primary molecule involved in the pathogenesis of CSF, but also an important marker for both the diagnosis and treatment of this disease.

We demonstrated the modification of epsilon-amino groups on human histone H3 by deoxycholyl adenylate. When using a small amount of deoxycholyl adenylate, only one adduct fragment, amino acid 3-8 with a deoxycholate adduct, was produced, suggesting that the epsilon-amino group of Lys4 had the highest reactivity. In addition, other proteins in cells also formed protein adducts through flexible lysine residues, and we identified those proteins on a two-dimensional proteome map by MALDI-TOF MS and nanoLC/ESI-MS/MS. Chenodeoxycholic acid, a primary bile acid, abundantly exists in the rat brain, and may tightly bind to some proteins. It is therefore very important for understanding the physiological role of brain bile acids to identify chenodeoxycholate-binding proteins. We have shown the benefit of a new extraction method coupled with a cleavable affinity gel, which consists of a cleavable disulfide linker and a protein-targeting molecule at the end of the linker connected to the polymer. We tried to capture chenodeoxycholate-binding proteins in rat brain tissue by using chenodeoxycholate-immobilized cleavable affinity gel, developed in our laboratory. Tubulin-alpha, tubulin-beta, actin-beta, and 14-3-3 protein were found as candidates for chenodeoxycholate-binding proteins in the cerebrum, midbrain, cerebellum, brain stem, and hippocampus. In addition, growth hormone was also captured with the above proteins in the pituitary; therefore, we focused on growth hormone among these binding protein candidates, and analyzed noncovalent binding of chenodeoxycholate with growth hormone by the affinity labeling method.

Since the 1980s, cancer cells have been considered to be derived from well-differentiated normal cells via multiple incidents of damage to their genome, especially in oncogenes or tumor suppressor genes, which accelerate proliferation or foster malignant phenotypes, such as the ability to invade the surrounding tissue or metastasize to distant organs. In the thyroid, a novel hypothesis of carcinogenesis, the "fetal cell carcinogenesis" hypothesis, in which thyroid cancer cells are derived from the remnants of fetal cells, instead of well-differentiated somatic cells, such as thyrocytes, by de-differentiation, is proposed. In this hypothesis, thyroid cancer cells are generated from three types of fetal thyroid cells, thyroid stem cells(TSCs), thyroblasts and prothyrocytes by proliferation without differentiation, which results in anaplastic, papillary and follicular carcinoma, respectively. Genomic alternations, such as RET/PTC and PAX8-PPARgamma1 rearrangements and a mutation in the BRAF gene, play an oncogenic role by preventing thyroid fetal cells from differentiating. This hypothesis well explains the clinical and biological features and recent molecular evidence of thyroid cancer. Further, it underscores the importance of identifying stem cells and clarifying the molecular mechanism of organ development. Such data will lead to better understanding of thyroid carcinogenesis and the establishment of more accurate diagnostic methods and more effective therapies. Analysis of molecular behavior in a single tumor cell will be a key technology in the future clinical pathology. Fetal cell science may be the leading research theme in the next few decades.

Precise pathohistologic and immunohistochemical investigations of the pancreas in elderly autopsy cases revealed that endocrine tumors are found very frequently. Some endocrine tumors of the pancreas may originate from Langerhans islets, although other endocrine tumors may develop from endocrine cells or stem cells with multiple differentiation ability and occur in the duct cells or acinar cells. This possibility may be supported by the evidence that ductular or tubular structures were found in or adjacent to tumors in about 60% of minute tumors and that hormone production was found in both duct cells and acinar cells based on immunohistochemical findings. The occurrence of ductuloinsular tumors, acinar endocrine cell tumors, and duct-acinar-islet cell tumors may also support these observations. Islets of Langerhans with diameter of 500 microm or greater, or islets with a mean +/- 2 SD or greater, were found around the tumors, suggesting the presence of factors that promote the growth of islets of Langerhans. Molecular biological investigations will further analyze the pathogenesis of endocrine tumors of the pancreas. There are three possible origins of endocrine tumors of the pancreas: Langerhans islets cells, ductular cells, and acinar cells.

Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.

Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. In this paper, we will review our recent studies on production, migration and survival of newly-generated neurons in the adult mouse brain. Although the precise mechanisms controlling the migration of neuroblasts remain unclear, some molecules related to cell adhesion, cytoskeletal regulation or attractive/repulsive cues have been shown to be involved in this process. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia using blood vessels as their scaffold. The majority of the newly-generated neurons are known to die before they are integrated into neuronal circuits. However, we found that their survival could be promoted by the long-term administration of donepezil, an acetylcholinesterase inhibitor that is widely used for the treatment of Alzheimer's disease. Understanding more precise and comprehensive mechanisms of adult neurogenesis should lead to future development of regenerative therapies for neuropsychiatric diseases.

Advancement of chemotherapeutic agents and introduction of molecular-targeted therapy have been improving the prognosis of malignant tumors. However, allogeneic hematopoietic cell transplantation (allo-HCT) still remains the sole curative therapy against chemotherapy-resistant hematological malignancies. Once it was found that full engraftment of donor's immune cells could bring sufficient graft-versus-leukemia/lymphoma(GVL)effects, reduced intensity preconditioning regimens that focus only on suppression of the recipient's immune system so as to allow donor graft engraftment have been introduced into clinics. This has expanded the number of patients eligible for allo-HCT, including elderly patients. Nevertheless, overall survival of patients with high-risk malignancies has not been sufficiently improved. Simple enhancement of donor-derived immunity would result in the increased risk of graft-versus-host disease (GVHD). Here, current and future strategies to selectively enhance GVL effects without inducing detrimental GVHD will be discussed in parallel with their background information and basic concepts.

Regenerative medicine, currently on the stage of research, implies important ethical issues. Current main stream is the embryonic stem cell research which implies destruction of embryo in order to derive ES cells. Is such a use (destruction) of a human embryo, which is called a "germ of human life" in Japanese Society, ethically permitted or not? If yes, in which conditions? Expected clinical use of ES cells and differentiated cells thereof requires therapeutic cloning, on which arises also the ethical permissibility. Such heavy ethical obstacle leads researchers to the utilization of adult stem cells. Recent appearance of iPS cell (induced pluri-potential stem cell) does not escape from ethical issues, although the destruction of embryo is avoided.