Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Proteostasis and resilience: on the interphase between individual's and intracellular stress.

A long proportion of the population is resilient to the negative consequences of stress. Glucocorticoids resulting from endocrine responses to stress are essential adaptive mediators, but also drive alterations to brain function, negatively impacting neuronal connectivity, synaptic plasticity, and memory-related processes. Recent evidence has indicated that organelle function and cellular stress responses are relevant determinant of vulnerability and resistance to environmental stress. At the molecular level, a fundamental mechanism of cellular stress adaptation is the maintenance of proteostasis, which also have key roles in sustaining basal neuronal function. Here, we discuss recent evidence suggesting that proteostasis unbalance at the level of the endoplasmic reticulum, the main site for protein folding in the cell, represents a possible mechanistic link between individuals and cellular stress.

The effects of intro-oral parathyroid hormone on the healing of tooth extraction socket: an experimental study on hyperglycemic rats.

Objective To investigate the effects of intro-oral injection of parathyroid hormone (PTH) on tooth extraction wound healing in hyperglycemic rats. Methodology 60 male Sprague-Dawley rats were randomly divided into the normal group (n=30) and DM group (n=30). Type 1 diabetes mellitus (DM) was induced by streptozotocin. After extracting the left first molar of all rats, each group was further divided into 3 subgroups (n=10 per subgroup), receiving the administration of intermittent PTH, continuous PTH and saline (control), respectively. The intermittent-PTH group received intra-oral injection of PTH three times per week for two weeks. A thermosensitive controlled-release hydrogel was synthesized for continuous-PTH administration. The serum chemistry was determined to evaluate the systemic condition. All animals were sacrificed after 14 days. Micro-computed tomography (Micro-CT) and histological analyses were used to evaluate the healing of extraction sockets. Results The level of serum glucose in the DM groups was significantly higher than that in the non-DM groups (p<0.05); the level of serum calcium was similar in all groups (p>0.05). Micro-CT analysis showed that the DM group had a significantly lower alveolar bone trabecular number (Tb.N) and higher trabecular separation (Tb.Sp) than the normal group (p<0.05). The histological analyses showed that no significant difference in the amount of new bone (hard tissue) formation was found between the PTH and non-PTH groups (p>0.05). Conclusions Bone formation in the extraction socket of the type 1 diabetic rats was reduced. PTH did not improve the healing of hard and soft tissues. The different PTH administration regimes (continuous vs. intermittent) had similar effect on tissue healing. These results demonstrated that the metabolic characteristics of the hyperglycemic rats produced a condition that was unable to respond to PTH treatment.

Emerging roles of the unfolded protein response (UPR) in the nervous system: A link with adaptive behavior to environmental stress?

Stressors elicit a neuroendocrine response leading to increased levels of glucocorticoids, allowing the organism to adapt to environmental changes and maintain homeostasis. Glucocorticoids have a broad effect in the body, modifying the activity of the immune system, metabolism, and behavior through the activation of receptors in the limbic system. Chronic exposition to stressors operates as a risk factor for psychiatric diseases such as depression and posttraumatic stress disorder. Among the cellular alterations observed as a consequence of environmental stress, alterations to organelle function at the level of mitochondria and endoplasmic reticulum (ER) are emerging as possible factors contributing to neuronal dysfunction. ER proteostasis alterations elicit the unfolded protein response (UPR), a conserved signaling network that re-establish protein homeostasis. In addition, in the context of brain function, the UPR has been associated to neurodevelopment, synaptic plasticity and neuronal connectivity. Recent studies suggest a role of the UPR in the adaptive behavior to stress, suggesting a mechanistic link between environmental and cellular stress. Here, we revise recent evidence supporting an evolutionary connection between the neuroendocrine system and the UPR to modulate behavioral adaptive responses.

The effects of intro-oral parathyroid hormone on the healing of tooth extraction socket: an experimental study on hyperglycemic rats

Abstract Objective To investigate the effects of intro-oral injection of parathyroid hormone (PTH) on tooth extraction wound healing in hyperglycemic rats. Methodology 60 male Sprague-Dawley rats were randomly divided into the normal group (n=30) and DM group (n=30). Type 1 diabetes mellitus (DM) was induced by streptozotocin. After extracting the left first molar of all rats, each group was further divided into 3 subgroups (n=10 per subgroup), receiving the administration of intermittent PTH, continuous PTH and saline (control), respectively. The intermittent-PTH group received intra-oral injection of PTH three times per week for two weeks. A thermosensitive controlled-release hydrogel was synthesized for continuous-PTH administration. The serum chemistry was determined to evaluate the systemic condition. All animals were sacrificed after 14 days. Micro-computed tomography (Micro-CT) and histological analyses were used to evaluate the healing of extraction sockets. Results The level of serum glucose in the DM groups was significantly higher than that in the non-DM groups (p<0.05); the level of serum calcium was similar in all groups (p>0.05). Micro-CT analysis showed that the DM group had a significantly lower alveolar bone trabecular number (Tb.N) and higher trabecular separation (Tb.Sp) than the normal group (p<0.05). The histological analyses showed that no significant difference in the amount of new bone (hard tissue) formation was found between the PTH and non-PTH groups (p>0.05). Conclusions Bone formation in the extraction socket of the type 1 diabetic rats was reduced. PTH did not improve the healing of hard and soft tissues. The different PTH administration regimes (continuous vs. intermittent) had similar effect on tissue healing. These results demonstrated that the metabolic characteristics of the hyperglycemic rats produced a condition that was unable to respond to PTH treatment.

Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion.

BACKGROUND: The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson's disease (PD). Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. METHODS: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats. RESULTS: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01). DAT mRNA expression showed a significant decrease (p < 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. CONCLUSIONS: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells.

Follow-Up of Peripheral IL-1ß and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery.

Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1ß and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1ß and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation.

Review on research of the phytochemistry and pharmacological activities of Celosia argentea

ABSTRACT Celosia argentea L., Amaranthaceae, is widely used as traditional medicine with a long history in China. It is a unique source of Semen Celosiae whose contributions include purging the hepatic pathogenic fire, improving eyesight, and treating other eye diseases. Over 79 compounds from this plant were isolated and identified, mainly including saponins, peptides, phenols, fatty acids, and amino acids, of which saponins have been considered as the characteristic and active constituents of Celosia argentea. Experimental evidences manifested that Celosia argentea, with its active compounds, possesses wide-reaching biological activities such as hepatoprotection, tumor treatment, anti-diarrhea, anti-diabetes, anti-oxidant, anti-hypertension, and for treatment of a number of eye diseases. The objective of the study was to provide an overview of the ethno-pharmacology, chemical constituents, pharmacology, and related clinical applications of Celosia argentea, and to reveal their therapeutic potentials, and secure an evidence base for further research works on Celosia argentea.

Identification of reference genes for gene expression normalization in safflower (Carthamus tinctorius)

ABSTRACT Safflower (Carthamus tinctorius L., Asteraceae) is an important oil crop and medicinal plant. Gene expression analysis is gaining importance in the research of safflower. Quantitative PCR has become a powerful method for gene study. Reference genes are one of the major qualification requirements of qPCR because they can reduce the variability. To identify the reference genes in safflower, nine candidate genes of the housekeeping genes were selected from the EST library of safflower constructed by our lab: CtACT (actin), CtGAPDH (glyceraldehyde 3-phosphate dehydrogenase), CtE1F4A (elongation factor 1 alpha), CtTUA (alpha-tubulin), CtTUB (beta-tubulin), CtPP2A (serine/threonine-protein phosphatase), CtE1F4A (eukaryotic initiation factor 4A), CtUBI (Ubiquitin), and Ct60S (60S acidic ribosomal protein). Expression stability was examined by qPCR across 54 samples, representing tissues at different flowering stages and two chemotype of safflower lines. We assessed the expression stability of these candidate genes by employing four different algorithms (geNorm, NormFinder, ΔCt approach, and BestKeeper) and found that CtUBI and Ct60S were the highly ranked candidate genes. CtUBI and Ct60S were used as reference genes to evaluate the expression of CtFAD2-10 and CtKASII. Our data suggest CtUBI and Ct60S could be used as internal controls to normalize gene expression in safflower.

El sistema antioxidante del glutatión en la etiopatología de la disfunción nigro-estriatal / Glutathione antioxidant system in the etiopathology of nigrostriatal dysfunction

La enfermedad de Parkinson es una enfermedad neurodegenerativa crónica que afecta a las personas de la tercera edad. En una minoría de los casos la enfermedad es de origen genético pero en el resto, la causa es idiopática. En este sentido, la acumulación de los radicales libres y la pérdida de la homeostasis del glutatión se han señalado como posibles agentes causales. El presente texto se propuso revisar las evidencias experimentales que apoyan la participación de los radicales libres y la pérdida de la homeostasis del glutatión en el comienzo y la progresión de la degeneración de la substantianigrapars compacta. El estrés oxidativo en la enfermedad de Parkinson´s puede estar relacionado con las propiedades pro-oxidantes intrínsecas de la dopamina y elevadas concentraciones de hierro en la substantianigrapars compacta, que promueven la oxidación de la dopamina y la generación de especies reactivas del oxígeno. Cualquier evento que desencadene estos mecanismos, genera un daño celular. La disminución del glutatión es una de las alteraciones bioquímicas más tempranas, detectadas en asociación con la enfermedad de Parkinson y se ha relacionado con la inhibición del complejo I de la cadena de transporte mitocondrial, daño oxidativo, activación glial, entre otros que favorecen la neurodegeneración. Estas evidencias sugieren la necesidad de mantener la homeostasis del glutatión en el sistema dopaminérgico y su vínculo con la etiología de la degeneración nigro-estriatal, lo que tiene una potencial aplicación en la práctica clínica.

Parkinson's disease is a chronic neurodegenerative condition affecting elderly persons. In a minority of cases the disease has a genetic origin, but in most the cause is idiopathic. Accumulation of free radicals and loss of glutathione homeostasis have been pointed at as possible causal agents. The purpose of the study was to review experimental evidence supporting the involvement of free radicals and loss of glutathione homeostasis in the outset and progress of substantia nigra pars compacta degeneration. Oxidative stress in Parkinson's disease may be related to the intrinsic pro-oxidant properties of dopamine and high iron concentrations in the substantia nigra pars compacta, promoting dopamine oxidation and the generation of reactive oxygen species. Any event triggering these mechanisms will cause cell damage. Glutathione reduction is one of the earliest biochemical alterations detected in association with Parkinson's disease, and it has been related to the inhibition of complex I of the mitochondrial transport chain, oxidative damage and glial activation, among other factors leading to neurodegeneration. This evidence points to the need to maintain glutathione homeostasis in the dopaminergic system, as well as its relationship to the etiology of nigrostriatal degeneration, of potential application in clinical practice.

El sistema antioxidante del glutatión en la etiopatología de la disfunción nigro-estriatal / Glutathione antioxidant system in the etiopathology of nigrostriatal dysfunction

La enfermedad de Parkinson es una enfermedad neurodegenerativa crónica que afecta a las personas de la tercera edad. En una minoría de los casos la enfermedad es de origen genético pero en el resto, la causa es idiopática. En este sentido, la acumulación de los radicales libres y la pérdida de la homeostasis del glutatión se han señalado como posibles agentes causales. El presente texto se propuso revisar las evidencias experimentales que apoyan la participación de los radicales libres y la pérdida de la homeostasis del glutatión en el comienzo y la progresión de la degeneración de la substantianigrapars compacta. El estrés oxidativo en la enfermedad de Parkinson´s puede estar relacionado con las propiedades pro-oxidantes intrínsecas de la dopamina y elevadas concentraciones de hierro en la substantianigrapars compacta, que promueven la oxidación de la dopamina y la generación de especies reactivas del oxígeno. Cualquier evento que desencadene estos mecanismos, genera un daño celular. La disminución del glutatión es una de las alteraciones bioquímicas más tempranas, detectadas en asociación con la enfermedad de Parkinson y se ha relacionado con la inhibición del complejo I de la cadena de transporte mitocondrial, daño oxidativo, activación glial, entre otros que favorecen la neurodegeneración. Estas evidencias sugieren la necesidad de mantener la homeostasis del glutatión en el sistema dopaminérgico y su vínculo con la etiología de la degeneración nigro-estriatal, lo que tiene una potencial aplicación en la práctica clínica(AU)

Parkinsons disease is a chronic neurodegenerative condition affecting elderly persons. In a minority of cases the disease has a genetic origin, but in most the cause is idiopathic. Accumulation of free radicals and loss of glutathione homeostasis have been pointed at as possible causal agents. The purpose of the study was to review experimental evidence supporting the involvement of free radicals and loss of glutathione homeostasis in the outset and progress of substantia nigra pars compacta degeneration. Oxidative stress in Parkinsons disease may be related to the intrinsic pro-oxidant properties of dopamine and high iron concentrations in the substantia nigra pars compacta, promoting dopamine oxidation and the generation of reactive oxygen species. Any event triggering these mechanisms will cause cell damage. Glutathione reduction is one of the earliest biochemical alterations detected in association with Parkinsons disease, and it has been related to the inhibition of complex I of the mitochondrial transport chain, oxidative damage and glial activation, among other factors leading to neurodegeneration. This evidence points to the need to maintain glutathione homeostasis in the dopaminergic system, as well as its relationship to the etiology of nigrostriatal degeneration, of potential application in clinical practice(AU)

Visualization of the ribosomal DNA (45S rDNA) of Indica rice with FISH on some phases of cell cycle and extended DNA fibers

The ribosomal DNA (45S rDNA) behaviors during the cell cycle were analyzed on interphase nuclei, prophases, metaphases, pachytene chromosomes and extended DNA fibers in rice (Oryza,sativa ssp.indica cv.Guangluai No.4) by using high-resolution fluorescent in situ hybridization (FISH). The results show that 45S rDNA is located at the ends of short arms of chromosomes 9 and 10. But the signals are much more intense on chromosome 9 than on chromosome 10 in metaphase. Pachytene chromosome has rDNA signal arrays on chromosome 9. Different phases are described and discussed. These results indicate that the activity of rDNA at individual loci may also vary through the cell cycle in rice. on extended DNA fibers, 45S rDNA signals appear as strings of numerous red spots, but some signals are missed in some regions, probably result from weak signals or intergenic spacers

Visualization of the ribosomal DNA (45S rDNA) of Indica rice with FISH on some phases of cell cycle and extended DNA fibers

The ribosomal DNA (45S rDNA) behaviors during the cell cycle were analyzed on interphase nuclei, prophases, metaphases, pachytene chromosomes and extended DNA fibers in rice (Oryza,sativa ssp.indica cv.Guangluai No.4) by using high-resolution fluorescent in situ hybridization (FISH). The results show that 45S rDNA is located at the ends of short arms of chromosomes 9 and 10. But the signals are much more intense on chromosome 9 than on chromosome 10 in metaphase. Pachytene chromosome has rDNA signal arrays on chromosome 9. Different phases are described and discussed. These results indicate that the activity of rDNA at individual loci may also vary through the cell cycle in rice. on extended DNA fibers, 45S rDNA signals appear as strings of numerous red spots, but some signals are missed in some regions, probably result from weak signals or intergenic spacers(AU)

Visualization of the ribosomal DNA (45S rDNA) of Indica rice with FISH on some phases of cell cycle and extended DNA fibers

The ribosomal DNA (45S rDNA) behaviors during the cell cycle were analyzed on interphase nuclei, prophases, metaphases, pachytene chromosomes and extended DNA fibers in rice (Oryza,sativa ssp.indica cv.Guangluai No.4) by using high-resolution fluorescent in situ hybridization (FISH). The results show that 45S rDNA is located at the ends of short arms of chromosomes 9 and 10. But the signals are much more intense on chromosome 9 than on chromosome 10 in metaphase. Pachytene chromosome has rDNA signal arrays on chromosome 9. Different phases are described and discussed. These results indicate that the activity of rDNA at individual loci may also vary through the cell cycle in rice. on extended DNA fibers, 45S rDNA signals appear as strings of numerous red spots, but some signals are missed in some regions, probably result from weak signals or intergenic spacers(AU)