Design, synthesis, and structure-activity relationship (SAR) of N-[7-(4-hydroxyphenoxy)-6-methylindan-4-yl]malonamic acids as thyroid hormone receptor ß (TRß) selective agonists.

Highly TRß selective thyromimetics have several potential therapeutic applications. Based on the novel indane derivative KTA-439 with high receptor (TRß) and organ (liver) selectivity, a series of thyroid hormone analogues were prepared, in which the isopropyl at the 3'-position was replaced with alkyl and aralkyl moieties of variable lengths and branches. Binding assays for these human TRs and reporter cell assays showed that 2-arylethyl derivatives had higher TRß selectivity than KTA-439. KTA-574, a representative 2-arylethyl derivative, had TRß specificity in a binding assay and exhibited full agonism in a reporter cell assay.

[Endocrinological aspects of diabetes mellitus in the elderly].

Glucose-mediated energy production in central nervous system(CNS) reduces in the elderly. The reduction is also observed in young patients with diabetes mellitus(DM). Deviated endocrinological function is observed in both the elderly and young patients with DM. The deviation is characterized by mechanism of adaptation to the insufficient energy production in CNS. The decrease of glucose-mediated energy production is accelerated by decrease of the activity of growth hormone-insulin-like growth factor 1 axis and of conversion of thyroxine to triiodothyronine. These decreases are suitable for adaptation to the insufficient CNS activity induced by energy deficiency. Glucagon- and catecholamine-induced increases in plasma glucose level contribute to increase energy production. Parathyroid hormone action is activated in the elderly, which contributes to the inhibition of excess signal transduction in energy-deficient CNS. These deviations are considered as adaptations to the energy deficiency observed in aged patients with DM.

Discovery of novel indane derivatives as liver-selective thyroid hormone receptor ß (TRß) agonists for the treatment of dyslipidemia.

Thyromimetics that specifically target TRß have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRß) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRß selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.

American ginseng improves neurocognitive function in senescence-accelerated mice: possible role of the upregulated insulin and choline acetyltransferase gene expression.

AIM: To investigate the effects of American ginseng on neurocognitive function and glucose regulation in senescence-accelerated mice. METHODS: Male senescence-resistant inbred strains (SAMR1) and senescence-prone inbred strains (SAMP10) mice were divided into five groups and fed either a control diet or an American ginseng-supplemented diet (1% or 2% g/g) from 6 weeks to 10 months of age. Bodyweight, levels of fasting plasma glucose (FPG) and grading scores were monitored every month and neurocognitive functions were evaluated at 9 months of age with a KUROBOX apparatus using a stress-free positive cue task. Gene expressions of peroxisome proliferator-activated receptor delta (PPAR-δ), insulin, choline acetyltransferase (ChAT) and amyloid precursor protein (APP) in the brain were measured by real-time quantitative reverse transcription polymerase chain reaction assays. RESULTS: American ginseng decreased FPG in SAMR1 mice, but increased FPG in SAMP10 mice. Correct visit ratios were higher in both SAMR1 and SAMP10 strains consuming an American ginseng-supplemented diet. Gene upregulation of insulin and ChAT in the brain, but not of PPAR-δ or APP, was evident in American ginseng-fed groups. CONCLUSION: Daily consumption of American ginseng induced an enhancement in neurocognitive function in senescence-accelerated mice, which could be related to the upregulation of insulin and ChAT gene expression in the brain. Geriatr Gerontol Int 2012; 12: 123-130.

{mu}-Crystallin, new candidate protein in endotoxin-induced uveitis.

PURPOSE. micro-Crystallin (CRYM) is a major taxon-specific lens protein. The purpose of this study was to investigate the function of CRYM in eyes of mice with endotoxin-induced uveitis (EIU). METHODS. EIU was induced by an injection of a lipopolysaccharide (LPS) into the footpad of male C57BL/6J, CRYM knockout (CRYM(-/-)), and wild-type (CRYM(+/+)) mice. The expression of CRYM in the iris-ciliary body (ICB) was investigated by Western blot analyses and real-time RT-PCR at 12 hours and 1, 3, and 5 days after the LPS injection. The number of cells that had infiltrated the anterior chamber (AC) of the CRYM(+/+) mice was compared to that in the CRYM(-/-) mice at 1, 3, 5, and 7 days. The expressions of the mRNA of interleukin (IL)-1alpha, IL-6, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage-colony stimulating factor (GM-CSF) in the ICB of the two groups of mice were compared. RESULTS. The mRNA of CRYM was upregulated at 12 hours after LPS injection, and CRYM protein increased at 3 days. The number of inflammatory cells in the AC of the CRYM(-/-) mice was not significantly different on day 1 from that in the CRYM(+/+) mice, but was significantly lower (17.9 +/- 1.6 vs. 27.1 +/- 2.4 cells/section) on day 5. Expression of the mRNA of IL-1alpha and -6 in the CRYM(-/-) mice was significantly lower than that in the CRYM(+/+) mice on day 5. CONCLUSIONS. CRYM plays an important role in the development of the second peak of murine EIU.

Lymphocytic infundibuloneurohypophysitis: long-term follow-up of a case cured with glucocorticoid.

OBJECTIVE: To report a case of infundibuloneurohypophysitis treated with steroid. CLINICAL PRESENTATION: A 65-year-old woman who was well until 4 weeks before admission and was not taking any medication presented with acute development of polydipsia and polyuria. Urinary volume was increased to 4,500 ml/day. She showed elevated serum osmolality and low urine osmolality, together with shortage of antidiuretic hormone. Magnetic resonance imaging (MRI) of the pituitary revealed marked nodular thickening of the neurohypophysis. Endocrinologically, anterior pituitary function appeared normal. Based on these examinations, she was diagnosed as having central diabetes insipidus due to lymphocytic infundibuloneurohypophysitis. INTERVENTION: Prednisolone (1 mg/kg/day, p.o.) and D-deaminovasopressin (5 microg/day, intranasal) were commenced. Ten days after the administration of the agents, MRI showed a dramatic improvement in the thickening of the neurohypophysis. Ten weeks later, abnormalities found in earlier MRI had disappeared. The drugs were withdrawn gradually, and diabetes insipidus ceased 25 weeks later. Recurrence was not seen in the subsequent MRI, and the function of the posterior pituitary gland was completely normalized even 7 years after discontinuation of treatments. CONCLUSION: This case shows that noninvasive diagnosis and appropriate steroid administration can effectively cure lymphocytic infundibuloneurohypophysitis; it is recommended with long-term follow-up.

Five cases of severe hyponatremia in the elderly successfully treated with low doses of hydrocortisone.

Hyponatremia is commonly defined as a serum sodium concentration of 135 mEq/L or less, which is reported to occur in 0.97-2.48% of hospitalized patients. Especially, in elderly patients, severe hyponatremia is sporadically developed without any complaints. Although a variety of causes of hyponatremia are documented, diagnosis of functional adrenal insufficiency is difficult because of a lack of the diagnostic criteria. In this case report, we present five cases of hyponatremia in the elderly, who were presumed to have functional adrenal insufficiency, successfully treated with low doses of hydrocortisone.

Leydig cell tumor and malignant lymphoma in a patient with nonclassical 21-hydroxylase deficiency.

A 46-year-old man was admitted in our hospital with hypoglycemia; his FPG was 43 mg/mL. Five years earlier, he underwent simultaneous surgeries for an adrenal adenoma, a benign Leydig cell tumor (LCT), and a malignant lymphoma. Based on the laboratory results, he was diagnosed as congenital adrenal hyperplasia (CAH) due to nonclassical 21-hydroxylase deficiency (21-OHD). On immunohistochemistry analysis using the antibody against adrenal-specific 11beta-hydroxylase antibody, the LCT showed both properties as a testicular cell and as an adrenal cell. The genetic background of 21-OHD might contribute to the development of malignant lymphoma. Such as a case of LCT and malignant lymphoma in a patient with 21-OHD seems to be rare.

Acromegaly accompanied by Turner syndrome with 47,XXX/45,X/46,XX mosaicism.

A 33-year-old woman was hospitalized for examination of edematous laryngopharynx. She was acromegalic. A pituitary adenoma with elevated serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) was detected, indicating acromegaly caused by GH-secreting pituitary adenoma. Multiple pigmented nevi were also noted without overt short stature and cubitus valgus. Chromosome analysis revealed that she had contracted Turner syndrome with 47,XXX/45,X/46,XX mosaicism. Transsphenoidal resection of the tumor decreased serum GH and IGF-I levels, but the edema was not improved. Both premature ovarian failure and hypertension appeared after surgery. This case may indicate the important relationships between GH/IGF-I and Turner syndrome.

Spontaneous remission of diabetes insipidus due to CNS sarcoidosis.

Central nervous system (CNS) sarcoidosis is a crucial disease and has a poor prognosis. A 58-year-old woman had acute development of polydipsia and polyuria. Her pituitary MRI demonstrated a swelling of pituitary gland and hypophyseal stalk. She was diagnosed as central diabetes insipidus (CDI) due to CNS sarcoidosis based on the examinations and pituitary MRI findings as well as a result of cutaneous biopsy. Uveitis and bilateral hilar lymphadenopathy were observed mildly throughout. However, CDI and pituitary MRI findings were getting recovered spontaneously without steroid treatment in a couple of months, suggesting an atypical clinical course of CNS sarcoidosis.

Atypical early onset of diabetes, deafness and lung cancer in a male patient with mitochondrial mutations in peripheral mononuclear cells.

As mitochondria play a major role in the conversion of dietary calories into usable energy, generating reactive oxygen species as a toxic byproduct, mitochondrial dysfunction plays a role in a wide range of age-related disorders and various forms of cancer. The present report concerns a heavy smoker who died of lung cancer at age 40. He also developed progressive diabetes and sensory hearing loss. Mitochondrial DNA sequence analysis revealed four mutations in peripheral mononuclear cells. Three were novel point mutations, including a mutation in ATP synthase F0 subunit 6 (ATP6). Mitochondrial mutations and smoking may have contributed to the development of atypical early onset of senescence-related diseases in this case.

Biphasic function of focal adhesion kinase in endothelial tube formation induced by fibril-forming collagens.

Migration and tube formation of endothelial cells are important in angiogenesis and require a coordinated response to the extra-cellular matrix (ECM) and growth factor. Since focal adhesion kinase (FAK) integrates signals from both ECM and growth factor, we investigated its role in angiogenesis. Type I and II collagens are fibril-forming collagens and stimulate human umbilical vein endothelial cells (HUVECs) to form tube structure. Although knockdown of FAK restrained cell motility and resulted in inhibition of tube formation, FAK degradation and tube formation occurred simultaneously after incubation with fibril-forming collagens. The compensation for the FAK degradation by a calpain inhibitor or transient over-expression of FAK resulted in disturbance of tube formation. These phenomena are specific to fibril-forming collagens and mediated via alpha2beta1 integrin. In conclusion, our data indicate that FAK is functioning in cell migration, but fibril-forming collagen-induced FAK degradation is necessary for endothelial tube formation.

Do PPARgamma Ligands Suppress the Growth of Cholangiocarcinoma or the Cholangiohepatitis Induced by the Tumor?

Cholangiocarcinoma is a predominantly fatal cancer, which can be difficult to treat. It has been reported that the administration of pioglitazone temporarily improved not only diabetic control, but also bile duct carcinoma-induced cholangiohepatitis. Pioglitazone is considered to have both direct and indirect mechanisms of action on the tumor-related hepatitis. Several molecules induced by thiazolidinedione, including Smad pathway-related molecules, adipokines, and other lipid metabolism-related proteins, may directly or indirectly suppress tumor development and/or tumor-induced cholangiohepatitis. Although the most frequent and critical side effect of thiazolidinedione is drug-induced hepatitis, it can probably be avoided by careful monitoring of serum hepatic enzyme levels. Thiazolidinedione should be considered for management of tumor-induced hepatitis in the presence of diabetes unless severe side effects occur.

Beneficial effects of pioglitazone on cholangiohepatitis induced by bile duct carcinoma.

Cholangiocarcinoma is a predominantly fatal cancer, which can be difficult to treat. We report a 73-year-old man who developed cholangiocarcinoma with cholangiohepatitis and diabetes. Administration of pioglitazone, peroxisome proliferator-activated receptor gamma (PPARgamma). agonist, improved not only diabetic control, but also the tumor-induced cholangiohepatitis, and improved the patient's quality of life. Although he finally died of obstructive jaundice, thiazolidinedione should be considered for treatment of tumor-induced hepatitis in the presence of diabetes, unless severe side effects occur.

mu-crystallin, a NADPH-dependent T(3)-binding protein in cytosol.

Thyroid hormone action is initiated through nuclear thyroid hormone receptors (TRs). Before the discovery of these nuclear receptors, possible major binding sites for thyroid hormones were thought to be cytosolic owing to high thyroid hormone-binding activity in crude cytosolic fractions. Several cytosolic thyroid hormone-binding proteins have been identified, including reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent 3,5,3'-triiodo-L-thyronine (T(3))-binding protein, also known as mu-crystallin, which was initially cloned as the ortholog of bacterial ornithine cyclodeaminase. The expression of mu-crystallin is developmentally regulated and cell-type specific. Recently, patients with nonsyndromic deafness were reported to have point mutations in the mu-crystallin gene. Cytosolic thyroid hormone-binding proteins, especially mu-crystallin, have roles in adaptation to environmental alterations by thyroid hormone, which might have a role in hearing function.