Hypothalamic Menin regulates systemic aging and cognitive decline.

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases.

Astrocytes are the most abundant cells in the brain. They have many important functions in the central nervous system (CNS), including the maintenance of glutamate and ion homeostasis, the elimination of oxidative stress, energy storage in glycogen, tissue repair, regulating synaptic activity by releasing neurotransmitters, and participating in synaptic formation. Astrocytes have special highly ramified structure. Their branches contact with synapses of neurons inwardly, with fine structure and wrapping synapses; their feet contact with blood vessels of brain parenchyma outward, almost wrapping the whole brain. The adjacent astrocytes rarely overlap and communicate with each other through gap junction channels. The ideal location of astrocytes enables them to sense the weak changes of their surroundings and provide the structural basis for the energy supply of neurons. Neurons and astrocytes are closely coupled units of energy metabolism in the brain. Neurons consume a lot of ATPs in the process of neurotransmission. Astrocytes provide metabolic substrates for neurons, maintain high activity of neuron, and facilitate information transmission of neurons. This article reviews the characteristics of glucose metabolism, lipid metabolism, and amino acid metabolism of astrocytes. The metabolic interactions between astrocytes and neurons, astrocytes and microglia were also detailed discussed. Finally, we classified analyzed the role of metabolic disorder of astrocytes in the occurrence and development of neurodegenerative diseases.

Application of antidepressants in depression: A systematic review and meta-analysis.

BACKGROUND: The type and quantities of antidepressants are increasing, but the efficacy and safety of first-line and emerging drugs vary between studies. In this article, we estimated the efficacy and safety of first-line and emerging antidepressants (anti-inflammatory drugs and ketamine). METHOD: ystematic search of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without language restriction for studies on the depression, depressive symptoms, antidepressants, fluoxetine (Prozac), paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, duloxetine, NSAIDs, anti-cytokine drugs or pioglitazone published before May 1st, 2019. Information on study characteristics, depression or depressive symptoms, antidepressants and the descriptive statistics (including efficacy and safety of antidepressants) was extracted independently by 2 investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using stratified meta-analysis and meta-regression. The response and remission of antidepressants were used as clinical evaluation indicators, and the evaluation criteria were clinical depression scales. OR value of antidepressants as assessed by meta-analysis. RESULTS: The literature search retrieved 5529 potentially relevant articles of which 49 studies were finally included. We compared the efficacy of antidepressants (seven first-line antidepressants (fluoxetine, paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, duloxetine), there kinds of anti-inflammatory drugs(NASIDs, cytokine-inhibitor, pioglitazone) and ketamine) by comparing the OR values. CONCLUSION: The three drugs with the highest OR value in response were NASID (OR = 3.62(1.58, 8.32)), venlafaxin (OR = 3.50(1.83, 6.70)) and ketamine (OR = 3.28(1.89, 5.68)), while the highest OR value in remission were NASID (OR = 3.17(1.60, 6.29)), ketamine (OR = 2.99(1.58, 5.67)) and venlafaxin (OR = 2.55(1.72, 3.78)). Through reading the literature, we found 69 SNPs associated with depression. Major depression was a debilitating disorder that could ultimately lead to enormous societal and economical challenge [1]. The number of person which affected by depression was up to 16% of the population worldwide. More than 300 million individuals were estimated to suffer depression these days [1,2]. Therefore, it is apparent that safety and effective treatments for depression are necessary. In the 1930 s, the first drug for schizophrenia was discovered. This finding was a landmark for the emerging of biological psychiatry. In the 1950 s, pharmacologists had stumbled upon the antidepressant effect of imipramine. Since then, every 30 years, the use of antidepressants had made a pulsatile leap. Selective serotonin reuptake inhibitors (SSRIs) are the most widely-prescribed psychiatric drugs for the treatment of depression. However, the efficacy was variable and incomplete: 60%-70% of the patients do not experience remission, while 30%-40% do not show a significant response [3,4]. Nevertheless, SSRIs, SNRIs (selective serotonin-norepinephrine reuptake inhibitors, which can block norepinephrine at the same time) and NaSSAs (norepinephrine and selective serotonin receptor agonist), constituted the first-line clinical drugs. Nearly 30 years after the outbreak of SSRIs, antidepressants have ushered in a new chapter. It has been found that anti-inflammatory drugs could also have the small and moderate antidepressant effect and it's widely discussed [5]. More than 40 anti-inflammatory drugs have been certificated to have antidepressant effects in preclinical and clinical studies [6]. The antidepressant that has been approved for use recently is ketamine. There is no comprehensive comparison of the efficacy of all these drugs. In this review, we tried to estimate the efficacy and safety of first-line antidepressants, anti-inflammatory drugs and ketamine. On the other hand, with the development of GWAS, SNPs related to depression have been reported, and the corresponding mechanisms have been elaborated, respectively. However, patients with these SNPs have not been treated with individualized drugs according to the mechanisms. We hope to push this process forward through the summary of this article. METHODS: Search Strategy and Study Eligibility.

Cyclin-Dependent Kinase 5-Dependent BAG3 Degradation Modulates Synaptic Protein Turnover.

BACKGROUND: Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer's disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were reexamined in search of candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. METHODS: Quantitative phosphoproteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays was used to investigate the associated regulatory signaling networks. Histological, electrochemical, and behavioral assays were performed in conditional knockout, small hairpin RNA-mediated knockdown, and AD-related mice models to evaluate the relevance of CDK5 to synaptic homeostasis and functions. RESULTS: Among candidates with known implications in synaptic modulations, BAG3 ranked the highest. CDK5-mediated phosphorylation on S297/S291 (mouse/human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such effects were reversed by ectopic BAG3 reexpression. CONCLUSIONS: Our results highlight that the neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.

Cyclin-dependent kinase 5-mediated phosphorylation of chloride intracellular channel 4 promotes oxidative stress-induced neuronal death.

Oxidative stress can cause apoptosis in neurons and may result in neurodegenerative diseases. However, the signaling mechanisms leading to oxidative stress-induced neuronal apoptosis are not fully understood. Oxidative stress stimulates aberrant activation of cyclin-dependent kinase 5 (CDK5), thought to promote neuronal apoptosis by phosphorylating many cell death-related substrates. Here, using protein pulldown methods, immunofluorescence experiments and in vitro kinase assays, we identified chloride intracellular channel 4 (CLIC4), the expression of which increases during neuronal apoptosis, as a CDK5 substrate. We found that activated CDK5 phosphorylated serine 108 in CLIC4, increasing CLIC4 protein stability, and accumulation. Pharmacological inhibition or shRNA-mediated silencing of CDK5 decreased CLIC4 levels in neurons. Moreover, CLIC4 overexpression led to neuronal apoptosis, whereas knockdown or pharmacological inhibition of CLIC4 attenuated H2O2-induced neuronal apoptosis. These results implied that CLIC4, by acting as a substrate of CDK5, mediated neuronal apoptosis induced by aberrant CDK5 activation. Targeting CLIC4 in neurons may therefore provide a therapeutic approach for managing progressive neurodegenerative diseases that arise from neuronal apoptosis.

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation.

Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1ß production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1ß receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1ß production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.

Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression.

Menin (MEN1) is a critical modulator of tissue development and maintenance. As such, MEN1 mutations are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin is abundantly expressed in the nervous system, little is known with regard to its function in the adult brain. Here, we demonstrate that neuron-specific deletion of Men1 (CcKO) affects dendritic branching and spine formation, resulting in defects in synaptic function, learning, and memory. Furthermore, we find that menin binds to the p35 promoter region to facilitate p35 transcription. As a primary Cdk5 activator, p35 is expressed mainly in neurons and is critical for brain development and synaptic plasticity. Restoration of p35 expression in the hippocampus and cortex of Men1 CcKO mice rescues synaptic and cognitive deficits associated with Men1 deletion. These results reveal a critical role for menin in synaptic and cognitive function by modulating the p35-Cdk5 pathway.

Male Men1 heterozygous mice exhibit fasting hyperglycemia in the early stage of MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited syndrome characterized by multiple tumors in the parathyroid glands, endocrine pancreas and anterior pituitary. Recent clinical studies have revealed a strong association between MEN1 syndrome and the risk of developing diabetes mellitus; however, the underlying mechanisms remain unknown. In this study, heterozygous Men1 knockout (Men1(+/-)) mice were used as MEN1 models to investigate MEN1-associated glucose metabolic phenotypes and mechanisms. Heterozygous deficiency of Men1 in 12-month-old male mice induced fasting hyperglycemia, along with increased serum insulin levels. However, male Men1(+/-) mice did not show insulin resistance, as evidenced by Akt activation in hepatic tissues and an insulin tolerance test. Increased glucose levels following pyruvate challenge and expression of key gluconeogenic genes suggested increased hepatic glucose output in the male Men1(+/-) mice. This effect could be partly due to higher basal serum glucagon levels, which resulted from pancreatic islet cell proliferation induced by heterozygous loss of Men1 Taken together, our results indicate that fasted male Men1(+/-) mice, in the early stage of development of MEN1, display glucose metabolic disorders. These disorders are caused not by direct induction of insulin resistance, but via increased glucagon secretion and the consequent stimulation of hepatic glucose production.

Low dose nicotine attenuates Aß neurotoxicity through activation early growth response gene 1 pathway.

Epidemiological studies indicate that smoking is negatively correlated with the incidence and development of Alzheimer's disease (AD). Nicotine was reported to be the active factor. However, the detailed mechanisms still remain to be fully elucidated. Early growth response gene 1 (EGR-1) plays important roles in several important biological processes such as promoting cell growth, differentiation, anti oxidative stress, and apoptosis, but few in the pathogenesis of AD. In the present study, we show that nicotine can activate the MAPK/ERK/EGR-1 signaling pathway partially through α7 nAChR. In addition, the up-regulation of EGR-1 by nicotine can also increase the phosphorylation of CyclinD1 which contributes to the attenuation of amyloid-ß (Aß(25-35)) -induced neurotoxicity. Although nicotine and Aß(25-35) can activate EGR-1, the expression of EGR-1 is down-regulated following treatment with nicotine and Aß(25-35). This study demonstrates that low dose nicotine attenuates Aß(25-35)-induced neurotoxicity in vitro and in vivo through activating EGR-1 pathway.

Cholesterol modulates function of connexin 43 gap junction channel via PKC pathway in H9c2 cells.

It has been shown that cholesterol modulates activity of protein kinase C (PKC), and PKC phosphorylates connexin 43 (Cx43) to regulate its function, respectively. However, it is not known whether cholesterol modulates function of Cx43 through regulating activity of PKC. In the present study, we demonstrated that cholesterol enrichment reduced the dye transfer ability of Cx43 in cultured H9c2 cells. Western blot analysis indicated that cholesterol enrichment enhanced the phosphorylated state of Cx43. Immunofluorescent images showed that cholesterol enrichment made the Cx43 distribution from condensed to diffused manner in the interface between the cells. In cholesterol enriched cells, PKC antagonists partially restored the dye transfer ability among the cells, downregulated the phosphorylation of Cx43 and redistributed Cx43 from the diffused manner to the condensed manner in the cell interface. In addition, reduction of cholesterol level suppressed PKC activity to phosphorylate Cx43 and restored Cx43 function in PKC agonist-treated cells. Furthermore, we demonstrated that cholesterol enrichment upregulated the phosphorylated state of Cx43 at Ser368, while PKC antagonists reversed the effect. Taken together, cholesterol level in the cells plays important roles in regulating Cx43 function through activation of the PKC signaling pathway.

Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel.

Chlorpromazine (CPZ) is a well-known antipsychotic drug, still widely being used to treat symptoms of schizophrenia, psychotic depression and organic psychoses. We have previously reported that CPZ activates the BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BKCa channels without changing its single channel amplitude. As BKCa channel is one of the molecular targets of brain ischemia, we explored a possible new use of this old drug on ischemic brain injury. In middle cerebral artery occlusion (MCAO) focal cerebral ischemia, a single intraperitoneal injection of CPZ at several dosages (5mg/kg, 10mg/kg and 20mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BKCa channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BKCa channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BKCa channels and merits exploration as a potential therapeutic agent for treating ischemic stroke.

Auditory sexual difference in the large odorous frog Odorrana graminea.

Acoustic communication is an important behavior in frog courtship. Male and female frogs of most species, except the concave-eared torrent frog Odorrana tormota, have largely similar audiograms. The large odorous frogs (Odorrana graminea) are sympatric with O. tormota, but have no ear canals. The difference in hearing between two sexes of the frog is unknown. We recorded auditory evoked near-field potentials and single-unit responses from the auditory midbrain (the torus semicircularis) to determine auditory frequency sensitivity and threshold. The results show that males have the upper frequency limit at 24 kHz and females have the upper limit at 16 kHz. The more sensitive frequency range is 3-15 kHz for males and 1-8 kHz for females. Males have the minimum threshold at 11 kHz (58 dB SPL), higher about 5 dB than that at 3 kHz for females. The best excitatory frequencies of single units are mostly between 3 and 5 kHz in females and at 7-8 kHz in males. The underlying mechanism of auditory sexual differences is discussed.

Surface-modified anodic aluminum oxide membrane with hydroxyethyl celluloses as a matrix for bilirubin removal.

Microporous anodic aluminum oxide (AAO) membranes were modified by 3-glycidoxypropyltrimethoxysilane to produce terminal epoxy groups. These were used to covalently link hydroxyethyl celluloses (HEC) to amplify reactive groups of AAO membrane. The hydroxyl groups of HEC-AAO composite membrane were further modified with 1,4-butanediol diglycidyl ether to link arginine as an affinity ligand. The contents of HEC and arginine of arginine-immobilized HEC-AAO membrane were 52.1 and 19.7mg/g membrane, respectively. As biomedical adsorbents, the arginine-immobilized HEC-AAO membranes were tested for bilirubin removal. The non-specific bilirubin adsorption on the unmodified HEC-AAO composite membranes was 0.8mg/g membrane. Higher bilirubin adsorption values, up to 52.6mg/g membrane, were obtained with the arginine-immobilized HEC-AAO membranes. Elution of bilirubin showed desorption ratio was up to 85% using 0.3M NaSCN solution as the desorption agent. Comparisons equilibrium and dynamic capacities showed that dynamic capacities were lower than the equilibrium capacities. In addition, the adsorption mechanism of bilirubin and the effects of temperature, initial concentration of bilirubin, albumin concentration and ionic strength on adsorption were also investigated.

[Expression of A-kinase anchor protein 95, cyclin E2, and connexin 43 in lung cancer tissue, clinical significance of their expression, and their expression correlation].

OBJECTIVE: To study the expression of A-kinase anchor protein 95 (AKAP95), cyclin E(2), and connexin 43 (Cx43) in lung cancer tissue, the clinical significance of their expression, and the expression correlation among the three proteins. METHODS: Fifty-one samples of lung cancer tissue were examined by immunohistochemistry to measure the expression of AKAP95, cyclin E2, and Cx43. RESULTS: The positive rate of AKAP95 expression in lung cancer tissue was significantly higher than that in paracancerous tissue (82.35% vs 33.33%, P < 0.05); AKAP95 expression was associated with the cell differentiation and histopathological type of lung cancer (P < 0.05). The positive rate of cyclin E(2) expression in lung cancer tissue was significantly higher than that in paracancerous tissue (43.14% vs 13.33%, P < 0.05); cyclin E(2) expression was associated with the lymph node metastasis and histopathological type of lung cancer (P < 0.05). The positive rate of Cx43 expression in lung cancer tissue was lower than that in paracancerous tissue (60.78% vs 80.00%); Cx43 expression was associated with the cell differentiation, lymph node metastasis, and histopathological type of lung cancer (P < 0.05). There was correlation between each two of AKAP95 expression, cyclin E(2) expression, and Cx43 expression in lung cancer tissue. CONCLUSION: High expression of AKAP95 and cyclin E(2) plays an important role in the occurrence and development of lung cancer. AKAP95 expression is associated with the cell differentiation and histopathological type of lung cancer, and cyclin E2 expression is associated with lymph node metastasis and histopathological type. There is correlation between each two of AKAP95 expression, cyclin E(2) expression, and Cx43 expression in lung cancer tissue.