El esqueleto como órgano endocrino: funciones metabólicas de la osteocalcina / The skeleton as an endocrine organ: metabolic functions of osteocalcin

El esqueleto es uno de los sistemas más grandes de un vertebrado y, como tal, es razonable especular que no puede funcionar aislado del resto del organismo. De hecho, sabemos que existen sistemas complejos de regulación cruzada entre el esqueleto y muchos otros órganos. Hoy poseemos herramientas que nos permiten realizar supresión genética en células o tejidos específicos. Esto nos ha permitido comprender cómo los órganos se comunican entre sí y ha revitalizado el concepto de fisiología del organismo como un todo. Efectivamente, los últimos años han sido testigos del descubrimiento de funciones inesperadas que ejerce el esqueleto y que afectan al organismo en su totalidad. Una de tales funciones reconocidas recientemente es el control del metabolismo energético, a través de la secreción de osteocalcina. La osteocalcina es una hormona producida por los osteoblastos que regula la secreción de insulina, la sensibilidad a esta hormona y el metabolismo energético. Los hallazgos iniciales suscitaron varias preguntas fundamentales sobre la naturaleza de la acción de la insulina sobre el hueso. Pero esto solo fue la punta del iceberg. Efectivamente, más adelante se descubrió, mediante el análisis de ratones que carecen del receptor de insulina (Ins R) solamente en osteoblastos, que la acción de la insulina sobre estas células favorecía la homeostasis de la glucosa en todo el cuerpo. Es importante destacar que esta función de la insulina en los osteoblastos opera mediante la regulación negativa de la carboxilación y la biodisponibilidad de la osteocalcina. Más aún, se observó que las vías de señalización de la insulina en los osteoblastos regulan positivamente no solo la formación sino también la resorción del hueso. Curiosamente, parece que las vías de señalización de la insulina en osteoblastos pueden inducir la activación de la osteocalcina mediante la estimulación de la actividad de los osteoclastos. De hecho, el bajo pH generado durante la resorción ósea es suficiente para desencadenar la descarboxilación (y subsiguiente activación) de la osteocalcina. En breve discutiremos dos nuevas proposiciones: 1) los osteoblastos son un blanco utilizado por la insulina para controlar la homeostasis de la glucosa en todo el organismo y 2) la resorción ósea desempeña un papel fundamental en la regulación de la activación de la osteocalcina. (AU)

The skeleton is one of the biggest systems in a vertebrate animal and, as such, it is reasonable to speculate that it cannot function isolated from the rest of the organism. In fact, we know that complex systems exist for the cross-regulation between the skeleton and several other organs. Today, we have the tools that allow us to perform genetic suppression in specific cells or tissues. This has allow us understand the mechanisms by which the organs communicate with each other and has revitalized the concept of organismal physiology as a whole. Studies conducted in recent years have uncovered unexpected functions performed by the skeleton. One of these is the control of global energy metabolism, through the secretion of osteocalcin, a protein produced by osteoblasts that acts as a hormone regulating insulin secretion, insulin sensitivity and energy expenditure. The evidence comes from the analysis of mice lacking insulin receptor (InsR) exclusively in osteoblasts. These mice have a global metabolic phenotype demonstrating that the action of insulin in osteoblasts promotes the homeostasis of glucose throughout the body. This action of insulin in osteoblasts is mediated by the negative regulation of the carboxylation (and bioavailability) of osteocalcin. The decarboxylation (and activation) of osteocalcin, in turn, occurs in the osteoclastic resorption pit. Briefly: the osteoblast is a target used by insulin to control the homeostasis of glucose throughout the body and bone resorption is the mechanism that regulates the activation of osteocalcin. (AU)

Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling

Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-beta-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.

Quinolone resistance and ornithine decarboxylation activity in lactose-negative Escherichia coli

Quinolones and fluoroquinolones are widely used to treat uropathogenic Escherichia coli infections. Bacterial resistance to these antimicrobials primarily involves mutations in gyrA and parC genes. To date, no studies have examined the potential relationship between biochemical characteristics and quinolone resistance in uropathogenic E. coli strains. The present work analyzed the quinolone sensitivity and biochemical activities of fifty-eight lactose-negative uropathogenic E. coli strains. A high percentage of the isolates (48.3%) was found to be resistant to at least one of the tested quinolones, and DNA sequencing revealed quinolone resistant determining region gyrA and parC mutations in the multi-resistant isolates. Statistical analyses suggested that the lack of ornithine decarboxylase (ODC) activity is correlated with quinolone resistance. Despite the low number of isolates examined, this is the first study correlating these characteristics in lactose-negative E. coli isolates.

Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers

Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.

IDH Mutation Analysis in Ewing Sarcoma Family Tumors

BACKGROUND: Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to yield alpha-ketoglutarate (alpha-KG) with production of reduced nicotinamide adenine dinucleotide (NADH). Dysfunctional IDH leads to reduced production of alpha-KG and NADH and increased production of 2-hydroxyglutarate, an oncometabolite. This results in increased oxidative damage and stabilization of hypoxia-inducible factor alpha, causing cells to be prone to tumorigenesis. METHODS: This study investigated IDH mutations in 61 Ewing sarcoma family tumors (ESFTs), using a pentose nucleic acid clamping method and direct sequencing. RESULTS: We identified four cases of ESFTs harboring IDH mutations. The number of IDH1 and IDH2 mutations was equal and the subtype of IDH mutations was variable. Clinicopathologic analysis according to IDH mutation status did not reveal significant results. CONCLUSIONS: This study is the first to report IDH mutations in ESFTs. The results indicate that ESFTs can harbor IDH mutations in previously known hot-spot regions, although their incidence is rare. Further validation with a larger case-based study would establish more reliable and significant data on prevalence rate and the biological significance of IDH mutations in ESFTs.

Actividad antimicrobiana del propóleos y efecto en las características fisicoquímicas y sensoriales en chorizos / Antimicrobial activity of propolis and its effect on the physicochemical and sensorial characteristics in sausages

Antecedentes: En la industria de alimentos es cada vez más común la utilización de aditivos naturales capaces de reemplazar los aditivos químicos, esto es debido a la tendencia a consumir alimentos más naturales y saludables. En la naturaleza existen diferentes compuestos que pueden cumplir dicha función, como el caso de los propóleos obtenidos en las colmenas de las abejas melíferas que presentan compuestos bioactivos con capacidad antimicrobiana y antioxidante y, por tanto, podría presentarse como una alternativa a la utilización de nitritos en productos cárnicos. Objetivo: Valorar la actividad antimicrobiana in-vitro del extracto etanólico de propóleos (EEP) sobre ciertas bacterias patógenas y su influencia en las características fisicoquímicas y sensoriales de chorizos. Métodos: Se realizó la extracción de los propóleos con alcohol etanólico al 96% y se determinó su actividad antimicrobiana in vitro sobre S. aureus, Salmonella spp., E. coli y Clostridium spp. Se prepararon chorizos de acuerdo a los siguientes tratamientos: (1) EEP 0.8mg/mL; (2) 0,2g/Kg de nitrito de sodio y eritorbato de sodio; (3) alcohol 96% (control) y se realizaron los análisis fisicoquímicos correspondientes a la determinación de ácido tiobarbitúrico (TBA) y bases volátiles de nitrógeno (BVT-N) y pruebas sensoriales cada ocho días durante cuatro semanas. Se realizó análisis de varianza de dos vías y prueba de Tukey, el nivel de significancia fue de p<0,05). Se observaron diferencias significativas (p<0,05) en los valores de TBA. Conclusiones: El EEP al 0,8% presenta actividad antimicrobiana para los microorganismos patógenos evaluados. Adicionalmente, las características fisicoquímicas y sensoriales del producto no difieren de los chorizos elaborados con nitrito

Pyruvate Dehydrogenase Kinase as a Potential Therapeutic Target for Malignant Gliomas

Metabolic aberrations in the form of altered flux through key metabolic pathways are the major hallmarks of several life-threatening malignancies including malignant gliomas. These adaptations play an important role in the enhancement of the survival and proliferation of gliomas at the expense of the surrounding normal/healthy tissues. Recent studies in the field of neurooncology have directly targeted the altered metabolic pathways of malignant tumor cells for the development of anti-cancer drugs. Aerobic glycolysis due to elevated production of lactate from pyruvate regardless of oxygen availability is a common metabolic alteration in most malignancies. Aerobic glycolysis offers survival advantages in addition to generating substrates such as fatty acids, amino acids and nucleotides required for the rapid proliferation of cells. This review outlines the role of pyruvate dehydrogenase kinase (PDK) in gliomas as an inhibitor of pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyruvate. An in-depth investigation on the key metabolic enzyme PDK may provide a novel therapeutic approach for the treatment of malignant gliomas.

The Effect of Agmatine on Expression of MMP2 and MMP9 in Cerebral Ischemia / 대한해부학회지

Agmatine is a primary amine formed by decarboxylation of L-arginine synthesized in the mammalian brain. Recent studies have shown that agmatine is neuroprotective in models of trauma and ischemia. The purpose of this study was to evaluate the effect of agmatine on the expression of MMP2 and MMP9, which are expressed in reperfusion injury following cerebral ischemia. Mice were subjected to 2 h middle cerebral artery occlusion and 22 h reperfusion. Agmatine (100 mg/kg) was administered intraperitoneally at the start of reperfusion. Agmatine treatment significantly reduced the immunoreactivity of MMP2 and MMP9 in the cortex, striatum, and penumbra on the ipsilateral side. The immunoreactivity of MMP2 and MMP9 was markedly lower in blood vessels of the agmatine-treated group than in the experimental control group. Immunoblot analysis showed that agmatine treatment decreased the expression of MMP2 and MMP9. After exogenous agmatine administration, the expression of agmatine was higher in the striatum and penumbra of the agmatine-treated group than in the experimental control group. The fluorescence intensity was markedly greater in blood vessels in the agmatine-treated group than in the experimental control group. These data suggest that agmatine might decrease the expression of MMP2 and MMP9 by regulating NOS activity, and thereby modulating NO synthesis.

A Case of Nonfunctioning Pancreatic Islet Cell Carcinomas in Adolescence

Neuroendocrine pancreatic tumors (NPTs) arise from the pancreatic islet cells and belong to the amine and precursor uptake and decarboxylation (APUD) system. These tumors are rare and account for only 1% to 5% of pancreatic tumor. The pancreas is an extremely uncommon site of neoplasia in children and adolescents. For this reason, our understanding of these tumors is still quite limited. Although the complete surgical resection is the key to successful management of all malignant adolescence pancreatic tumors, the information on the possible role of chemotherapy and radiation in recurrent, unresectable, or metastatic cases is purely anecdotal. The 17-year-old man transferred to our hospital with abnormal ultrasonographic findings. Result of abdominal ultrasonographic examination showed a mass in the upper abdomen. He presented with 6months history of intermittent abdominal pain and vomiting and diarrhea. A computed tomography (CT) scan and magnetic resonance showed a 4.5 x 6 cm mass in the head of the pancreas. An ultrasound-guided core biopsy confirmed an pancreatoblastoma or pancreas islet cell tumor. On operative findings, there was locally advanced, unresectable tumor within the pancreatic head. We report a 17-years-old man patient with non-functional panceratic islet cell carcinoma.

Expression of Neuroendocrine Cells in the Prostate of Rat and Guinea Pig after Orchiectomy / 대한비뇨기과학회지

PURPOSE: Neuroendocrine cells, also referred to as amine precursor uptake and decarboxylation (APUD) cells, in the prostate gland are serotonin and peptide containing cells, which are thought to play an important role in the regulation of growth, cellular differentiation and homeostasis. The expressions of neuroendocrine cells in the prostate differ between species and pathological conditions of the prostate. Androgen is believed to be a major effective material toward the prostate, its role in neuroendocrine cells is uncertain. The objective of this study was to investigate the effects of blockade of androgen on neuroendocrine cells in the prostate of rats and guinea pigs. MATERIALS AND METHODS: Rats and guinea pigs underwent an orchiectomy, and their prostate glands removed at 0 (control), 2 (2-week group) and 6 (6-week group) weeks after the orchiectomy. Each prostate tissue was examined both microscopically and with immunohistochemistry using synaptophysin, chromogranin A and serotonin. RESULTS: In the rat prostate glands, fewer neuroendocrine cells were stained with chromogranin A compared to the other two monoclonal antibodies. Although some atrophy of the glandular structure was presented grossly and microscopically in the castration groups, there was no difference in the chromogranin A immunoreactivity between the control, 2-week and 6-week groups. In the guinea pig prostate glands, few neuroendocrine cells were stained with either synaptophysin or serotonin. Glandular atrophy presented in the castration groups. There was no difference between the control, 2-week and 6-week groups in the immunoreactivities of the synaptophysin and serotonin monoclonal antibodies. CONCLUSIONS: The immunoreactivities of the neuroendocrine cells of rats and guinea pigs were different from those in humans and from each other. Neuroendocrine cells in the prostate of rats and guinea pigs exist only in small numbers, and seem to be independent of androgen.

Expression of Neuroendocrine Cells in the Prostate of Rat and Guinea Pig after Orchiectomy / 대한비뇨기과학회지

PURPOSE: Neuroendocrine cells, also referred to as amine precursor uptake and decarboxylation (APUD) cells, in the prostate gland are serotonin and peptide containing cells, which are thought to play an important role in the regulation of growth, cellular differentiation and homeostasis. The expressions of neuroendocrine cells in the prostate differ between species and pathological conditions of the prostate. Androgen is believed to be a major effective material toward the prostate, its role in neuroendocrine cells is uncertain. The objective of this study was to investigate the effects of blockade of androgen on neuroendocrine cells in the prostate of rats and guinea pigs. MATERIALS AND METHODS: Rats and guinea pigs underwent an orchiectomy, and their prostate glands removed at 0 (control), 2 (2-week group) and 6 (6-week group) weeks after the orchiectomy. Each prostate tissue was examined both microscopically and with immunohistochemistry using synaptophysin, chromogranin A and serotonin. RESULTS: In the rat prostate glands, fewer neuroendocrine cells were stained with chromogranin A compared to the other two monoclonal antibodies. Although some atrophy of the glandular structure was presented grossly and microscopically in the castration groups, there was no difference in the chromogranin A immunoreactivity between the control, 2-week and 6-week groups. In the guinea pig prostate glands, few neuroendocrine cells were stained with either synaptophysin or serotonin. Glandular atrophy presented in the castration groups. There was no difference between the control, 2-week and 6-week groups in the immunoreactivities of the synaptophysin and serotonin monoclonal antibodies. CONCLUSIONS: The immunoreactivities of the neuroendocrine cells of rats and guinea pigs were different from those in humans and from each other. Neuroendocrine cells in the prostate of rats and guinea pigs exist only in small numbers, and seem to be independent of androgen.

Paraganglioma of the Bladder / 대한비뇨기과학회지

Paragangliomas are rare tumors of a neural crest origin, and belong to the amine- precursor-uptake decarboxylation (APUD) system. The great majority of paraganglioma are in the adrenal medulla. The majority of extraadrenal sites arise near the adrenal or along the nerve plexuses. Paragangliomas are only occasionally found in the wall of the bladder. Their preoperative diagnosis is suspected from a clinical history and an estimation of catecholamines, or their metabolic by-products, in a twenty-four-hour urine sample. The correct diagnosis is not made in the majority of cases because the tumors are frequently silent with regard to hormonal activity. Therefore, an excretory urogram, arteriography and cystoscopy, including biopsy, are important procedures for their preoperative diagnosis. We report a case of paraganglioma arising in the bladder wall, with brief review of literatures.

A Case of Multicentric Duodenal Carcinoid / 대한소화기내시경학회지

Carcinoid tumors are the most common endocrine tumors of gastrointestinal tract. Argentaffin cells are the origin of carcinoids. These cells belong to the amino precursor uptake and decarboxylation (APUD) system. These cells give the tumor its most distinguishing feature: the ability to produce biogenic amines and polypeptide hormones that, in turn, give rise to the dramatic carcinoid syndrome. We treated a case of multi-centric carcinoid tumor of the duodenum in a 63-year-old male patient. He was admitted to the hospital because of epigastric pain. On the gastrofiberscopic examination, 1.0 x1.5 cm and 0.7 x0.8 cm sized two polyps (Yamada type II, I) were noticed on the duodenal bulb. The biopsy specimen showed carcinoid tumors of different histologic types. The level of 24-hour urine 5-HIAA of this case was normal. He was treated with subtotal gastrectomy with Billroth-II anastomosis. We report this case with literature review.