Miracle-dz/UniFAR-FTUs huggingface dataset:
D2 dopamine receptor expression and trafficking is regulated through direct interactions with ZIP

We have used the yeast two‐hybrid system to identify protein kinase C‐ζ interacting protein (ZIP) as a novel interacting protein for the D2 dopamine receptor (DAR). This interaction was identified by screening a rat brain cDNA library using the third intracellular loop of the D2 DAR as bait. A partial‐length cDNA encoding ZIP was isolated and characterized as specifically interacting with the third intracellular loop of the D2 DAR, but not with the third intracellular loops of other DAR subtypes. Biochemical confirmation of the ZIP–D2 DAR interaction was obtained by expressing the full‐length ZIP and D2 DAR proteins in mammalian cells and demonstrating that they could be co‐immunoprecipitated. We further showed that ZIP and the D2 DAR could be co‐immunoprecipitated from endogenous brain tissues. Immunohistochemical analyses further revealed that ZIP and the D2 DAR were extensively co‐localized within numerous neurons in various brain regions. ZIP exists as three protein isoforms of varying length, which are derived from alternative RNA splicing. All three isoforms were found to interact with the D2 DAR, which allowed for the delineation of the receptor interacting domain to within 38 residues of ZIP. Functionally, over‐expression of ZIP was found to result in decreased expression of the D2 DAR with a corresponding decrease in receptor modulation of cAMP accumulation. Confocal microscopy revealed that ZIP over‐expression also lead to an intracellular accumulation of D2 DAR protein in lysosome compartments. These results suggest that ZIP can physically interact with the D2 DAR leading to increased intracellular trafficking to lysosomes with subsequent down‐regulation of receptor expression and function.
Glucose promotes caspase‐dependent delayed cell death after a transient episode of oxygen and glucose deprivation in SH‐SY5Y cells

Brain ischemia causes neuronal cell death by several mechanisms involving necrotic and apoptotic processes. The contributions of each process depend on conditions such as the severity and duration of ischemia, and the availability of ATP. We examined whether glucose affected the development of apoptosis after transient ischemia, and whether this was sensitive to caspase inhibition. Retinoic acid‐differentiated SH‐SY5Y human neuroblastoma cells were subjected to oxygen and glucose deprivation for 15 h followed by various periods of reoxygenation in either the presence or absence of glucose. Oxygen and glucose deprivation induced cell death in the hours following reoxygenation, as detected by propidium iodide staining. At the end of the period of oxygen and glucose deprivation, both cytochrome c and apoptosis‐inducing factor translocated from mitochondria to cytosol. Reoxygenation in the presence of glucose accelerated cell death, and enhanced caspase‐3 activity and apoptosis. The glucose‐dependent increase in apoptosis was prevented by treatment with the caspase inhibitor zVAD‐fmk, but not with calpeptin, a calpain inhibitor. Nevertheless, both zVAD‐fmk and calpeptin decreased cell death in the glucose‐treated group. ATP levels dropped dramatically after oxygen and glucose deprivation, but recovered steadily thereafter, and were significantly higher at 6 h of reoxygenation in the glucose‐treated group. This indicates that energy recovery may promote the glucose‐dependent cell death. We conclude that glucose favours the development of caspase‐dependent apoptosis during reoxygenation following oxygen and glucose deprivation.
HIV‐1 viral envelope glycoprotein gp120 produces oxidative stress and regulates the functional expression of multidrug resistance protein‐1 (Mrp1) in glial cells

Brain human immunodeficiency virus type‐1 (HIV‐1) infection is associated with oxidative stress, which may lead to HIV‐1 encephalitis, a chronic neurodegenerative condition. In vitro, oxidative stress can be induced in glial cells by exposure to HIV‐1 envelope protein glycoprotein (gp120). Multidrug resistance proteins (Mrps) are known to efflux endogenous substrates (i.e. GSH and GSSG) involved in cellular defense against oxidative stress. Altered GSH/GSSG export may contribute to oxidative damage during HIV‐1 encephalitis. At present, it is unknown if gp120 exposure can alter the functional expression of Mrp isoforms. Heat‐shock protein 70, inducible nitric oxide synthase, intracellular GSSG, 2′,7′‐dichlorofluorescein fluorescence, and extracellular nitrite were increased in primary cultures of rat astrocytes triggered with gp120, suggesting an oxidative stress response. RT‐PCR and immunoblot analysis demonstrated increased Mrp1 mRNA (2.3‐fold) and protein (2.2‐fold), respectively, in gp120 treated astrocytes while Mrp4 mRNA or protein expression was not changed. Cellular retention of 2′,7′‐bis‐(2‐carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein, an established Mrp substrate, was reduced (twofold) in gp120‐treated astrocytes, suggesting increased Mrp‐mediated transport. In addition, GSH and GSSG export were enhanced in gp120‐triggered cells. These data suggest that gp120 can up‐regulate Mrp1, but not Mrp4, functional expression in cultured astrocytes. Our observation of increased GSH/GSSG efflux in response to gp120 treatment implies that Mrp isoforms may be involved in regulating the oxidative stress response in glial cells.
Hypertension and socioeconomic status

Purpose of review The impact of socioeconomic status on hypertension is complicated and unclear. In this article, we review the findings of recently published studies pertaining to the association between socioeconomic status and hypertension. Specifically, we focus on several potentially modifiable modes of pathogenesis involved in this association, including education, occupation, and social environment. We also review several mechanisms through which the effects of socioeconomic status on hypertension may be mediated. Recent findings Several modifiable socioeconomic determinants, such as education and occupation, are associated with hypertension. Additional socioeconomic status markers such as urban or rural dwelling and individual, local or national economic conditions are also associated with hypertension, although these associations are complicated and at times somewhat contradictory. Possible explanations for this impact include awareness of hypertension prevention and control and better accessibility and adherence to medical treatment among higher socioeconomic status groups, as well as low birth weight and higher job strain among lower socioeconomic status groups. Summary Low socioeconomic status is associated with higher blood pressure. There is a need to develop and test culturally appropriate interventions to reduce the prevalence of hypertension among these populations to minimize the resultant cardiovascular morbidity and mortality.
Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease resulting in progressive cognitive decline. Amyloid plaque deposits consisting specifically of β‐amyloid peptides that have formed fibrils displaying β‐pleated sheet conformation are associated with activated microglia and astrocytes, are colocalized with C1q and other complement activation products, and appear at the time of cognitive decline in AD. Amyloid precursor protein (APP) transgenic mouse models of AD that lack the ability to activate the classical complement pathway display less neuropathology than do the APPQ+/+ mice, consistent with the hypothesis that complement activation and the resultant inflammation may play a role in the pathogenesis of AD. Further investigation of the presence of complement proteins C3 and C4 in the brain of these mice demonstrate that both C3 and C4 deposition increase with age in APPQ+/+ transgenic mice, as expected with the age‐dependent increase in fibrillar β‐amyloid deposition. In addition, while C4 is predominantly localized on the plaques and/or associated with oligodendrocytes in APPQ+/+ mice, little C4 is detected in APPQ−/− brains consistent with a lack of classical complement pathway activation because of the absence of C1q in these mice. In contrast, plaque and cell associated C3 immunoreactivity is seen in both animal models and, surprisingly, is higher in APPQ−/− than in APPQ+/+ mice, providing evidence for alternative pathway activation. The unexpected increase in C3 levels in the APPQ−/− mice coincident with decreased neuropathology provides support for the hypothesis that complement can mediate protective events as well as detrimental events in this disease. Finally, induced expression of C3 in a subset of astrocytes suggests the existence of differential activation states of these cells.
Gender differences and estrogen effects in parkin null mice

Estrogens are considered neurotrophic for dopamine neurons. Parkinson’s disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild‐type (WT) and parkin null mice (PK−/−). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl‐2/Bax, chaperones, and GSH), but some of these inter‐sex differences disappear in PK−/−. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK−/− mice. Neuronal cultures from midbrain of WT and PK−/− mice were treated with estradiol from 10 min to 48 h. Short‐term treatments activated the mitogen‐activated protein kinase pathway of WT and PK−/− neurons and the phosphatidylinositol 3′‐kinase/AKT/glycogen synthase kinase‐3 pathway of WT but not of PK−/− cultures. Long‐term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK−/− cultures. The levels of estrogen receptor‐α were elevated in midbrain cultures and in the striatum of adult PK−/− male mice, suggesting that suppression of parkin changes the estrogen receptor‐α turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin‐related Parkinson’s disease patients.
Role of histamine in short‐ and long‐term effects of methamphetamine on the developing mouse brain

With the rise in methamphetamine (MA) use among women of childbearing age, the potential consequences of MA exposure to the developing brain for cognition in adulthood is a major concern. Histamine might mediate these MA effects. Following MA administration in neonatal mice, histamine levels in brain were elevated and the hypothalamic‐pituitary‐adrenal axis was activated. Co‐administration of MA with the H3 receptor agonist immepip antagonized these effects. The effects of MA on histamine levels and on hypothalamic‐pituitary‐adrenal axis activation at P20 were more pronounced in female than male mice. These sex differences could have contributed to the increased susceptibility of female mice to the detrimental long‐term cognitive effects of MA and the H3/H4 antagonist thioperamide. Following behavioral testing, mice neonatally treated with MA or thioperamide showed reduced levels of the dendritic marker microtubule‐associated protein 2 in the CA3 region of the hippocampus and the enthorhinal cortex. This was not seen in mice neonatally treated with immepip and MA who did not show cognitive impairments, suggesting that these brain areas might be particularly important for the long‐term effects of MA on cognitive function. These data support a role for histamine in the effects of MA on the developing brain.
TNF‐α‐mediates neuroprotection against glutamate‐induced excitotoxicity via NF‐κB‐dependent up‐regulation of KCa2.2 channels

Previous studies have shown that tumor necrosis factor‐alpha (TNF‐α) induces neuroprotection against excitotoxic damage in primary cortical neurons via sustained nuclear factor‐kappa B (NF‐κB) activation. The transcription factor NF‐κB can regulate the expression of small conductance calcium‐activated potassium (KCa) channels. These channels reduce neuronal excitability and as such may yield neuroprotection against neuronal overstimulation. In the present study we investigated whether TNF‐α‐mediated neuroprotective signaling is inducing changes in the expression of small conductance KCa channels. Interestingly, the expression of KCa2.2 channel was up‐regulated by TNF‐α treatment in a time‐dependent manner whereas the expression of KCa2.1 and KCa2.3 channels was not altered. The increase in KCa2.2 channel expression after TNF‐α treatment was shown to be dependent on TNF‐R2 and NF‐κB activation. Furthermore, activation of small conductance KCa channels by 6,7‐dichloro‐1H‐indole‐2,3‐dione 3‐oxime or cyclohexyl‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐pyrimidin‐4‐yl]‐amine‐induced neuroprotection against a glutamate challenge. Treatment with the small conductance KCa channel blocker apamin or KCa2.2 channel siRNA reverted the neuroprotective effect elicited by TNF‐α. We conclude that treatment of primary cortical neurons with TNF‐α leads to increased KCa2.2 channel expression which renders neurons more resistant to excitotoxic cell death.
Role of Src in ligand‐specific regulation of δ‐opioid receptor desensitization and internalization

The opioid receptors are a member of G protein‐coupled receptors that mediate physiological effects of endogenous opioid peptides and structurally distinct opioid alkaloids. Although it is well characterized that there is differential receptor desensitization and internalization properties following activation by distinct agonists, the underlying mechanisms remain elusive. We investigated the signaling events of δ‐opioid receptor (δOR) initiated by two ligands, DPDPE and TIPP. We found that although both ligands inhibited adenylyl cyclase (AC) and activated ERK1/2, only DPDPE induced desensitization and internalization of the δOR. We further found that DPDPE, instead of TIPP, could activate GRK2 by phosphorylating the non‐receptor tyrosine kinase Src and translocating it to membrane receptors. Activation of GRK2 led to the phosphorylation of serine residues in the C‐terminal tail, which facilitates β‐arrestin1/2 membrane translocation. Meanwhile, we also found that DPDPE promoted β‐arrestin1 dephosphorylation in a Src‐dependent manner. Thus, DPDPE appears to strengthen β‐arrestin function by dual regulations: promoting β‐arrestin recruitment and increasing β‐arrestin dephosphorylation at the plasma membrane in a Src‐dependent manner. All effects initiated by DPDPE could be abolished or suppressed by PP2, an inhibitor of Src. Morphine, which has been previously shown to be unable to desensitize or internalize δOR, also behaved as TIPP in failure to utilize Src to regulate δOR signaling. These findings point to the existence of agonist‐specific utilization of Src to regulate δOR signaling and reveal the molecular events by which Src modulates δOR responsiveness.
Heart failure in the ethnic minorities

Purpose of review Ethnic minority groups constitute increasing proportions of the population in western countries. Heart failure is increasingly prevalent worldwide and is associated with significant morbidity and mortality. The purpose of this review is to discuss the limited data on heart failure in the ethnic minority groups. Recent findings South Asians have more coronary risk factors that may increase the risk for premature coronary heart disease leading to development of heart failure at a younger age. In the Chinese, hypertension remains an important cause of heart failure and recent data suggest that heart failure with preserved systolic function is common. African–Americans have a higher prevalence of heart failure than whites, present with heart failure at younger ages, and heart failure in them is less likely to be due to coronary heart disease. Findings from a randomized controlled trial conducted specifically on African–Americans support the addition of the combination of isosorbide dinitrate and hydralazine to standard medical regimen for black patients with heart failure. Aboriginal people are more likely than nonaboriginal people to have less access to healthcare and to have a higher disease burden for atherosclerosis. Heart failure is more prevalent in aboriginal than in the nonaboriginal counterparts. Summary There are important differences across ethnic groups in the causes of heart failure and response to treatment. Given the likely increasing frequency of heart failure in these populations and an increasingly multiethnic world, additional studies on heart failure across different ethnic groups are warranted.
An Update on Monoclonal Antibody Therapies in Multiple Sclerosis

Multiple sclerosis (MS) is a complex disease that causes a great deal of disability, especially in the young adult population. There have been several immunomodulatory agents that have been approved by the Food and Drug Administration for MS, including glatiramer acetate, interferon-β1a and -β1b, mitoxantrone, and corticosteroids. The effectiveness of these therapies has not been optimal, and drugs, such as monoclonal antibodies, that more selectively target the pathogenetic process of MS have been sought. These agents have their own intrinsic limitations such as systemic inflammatory reactions, induction of neutralizing antiantibodies, and even life-threatening infectious processes. The agent that has been in the forefront of the discussion is natalizumab, a monoclonal antibody (mAb) against α4 integrin, which shows much promise in suppressing MS activity. However, 3 individuals treated with natalizumab developed a life-threatening infection, progressive multifocal leukoencephalopathy. This article reviews the role of mAbs in the treatment of MS, particularly their advantages over other drugs and their limitations, which have to be overcome for these agents to be at the forefront in the treatment of MS.
The glutamatergic nature of TRPV1‐expressing neurons in the spinal dorsal horn

The transient receptor potential vanilloid receptor 1 (TRPV1) is expressed on primary afferent terminals and spinal dorsal horn neurons. However, the neurochemical phenotypes and functions of TRPV1‐expressing post‐synaptic neurons in the spinal cord are not clear. In this study, we tested the hypothesis that TRPV1‐expressing dorsal horn neurons are glutamatergic. Immunocytochemical labeling revealed that TRPV1 and vesicular glutamate transporter‐2 were colocalized in dorsal horn neurons and their terminals in the rat spinal cord. Resiniferatoxin (RTX) treatment or dorsal rhizotomy ablated TRPV1‐expressing primary afferents but did not affect TRPV1‐ and vesicular glutamate transporter‐2‐expressing dorsal horn neurons. Capsaicin significantly increased the frequency of glutamatergic spontaneous excitatory post‐synaptic currents and miniature excitatory post‐synaptic currents in almost all the lamina II neurons tested in control rats. In RTX‐treated or dorsal rhizotomized rats, capsaicin still increased the frequency of spontaneous excitatory post‐synaptic currents and miniature excitatory post‐synaptic currents in the majority of neurons examined, and this effect was abolished by a TRPV1 blocker or by non‐NMDA receptor antagonist. In RTX‐treated or in dorsal rhizotomized rats, capsaicin also produced an inward current in a subpopulation of lamina II neurons. However, capsaicin had no effect on GABAergic and glycinergic spontaneous inhibitory post‐synaptic currents of lamina II neurons in RTX‐treated or dorsal rhizotomized rats. Collectively, our study provides new histological and functional evidence that TRPV1‐expressing dorsal horn neurons in the spinal cord are glutamatergic and that they mediate excitatory synaptic transmission. This finding is important to our understanding of the circuitry and phenotypes of intrinsic dorsal horn neurons in the spinal cord.
Baseline severity of depression predicts antidepressant drug response relative to escitalopram

Objective: The intent of this pooled analysis was to determine the relationship between baseline depression symptom severity and treatment response for escitalopram compared to that for other pooled antidepressant medications (citalopram, duloxetine, fluoxetine, paroxetine, sertraline and venlafaxine). Methods: Data were pooled from controlled clinical trials comparing escitalopram with other antidepressants for the treatment of major depression. The 15 trials meeting the inclusion criteria comprised 2,216 patients treated with escitalopram and 2,085 treated with one of the other antidepressants. The primary outcome measure of change from baseline to week 8 in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score was analyzed by an analysis of covariance, using the method of last-observation-carried-forward for missing values and adjusting for baseline and center values. Results: There was a significant interaction between baseline MADRS total score and treatment group (p = 0.0208). Response to escitalopram was stable regardless of baseline severity. For the pooled active comparators, response decreased with increasing baseline symptom severity. This differential efficacy of escitalopram with increasing symptom severity was confirmed by the analyses of the pooled 24-item Hamilton Depression Rating Scale (HAMD-24) results. A HAMD-24 single item analysis indicated that the sum of the baseline psychomotor retardation and hopelessness item scores significantly predicted which patients would benefit from treatment with escitalopram versus a comparator. Conclusion: Newer generation antidepressant medications clearly differ in their efficacy as a function of baseline symptom severity. The selective serotonin reuptake inhibitor escitalopram had superior efficacy in the treatment of more severe depression, perhaps attributable to differential efficacy related to symptoms of negativistic thinking.
VASCULAR SYSTEM OF THE HUMAN SPINAL CORD

This report is that of a study made on a number of human spinal cords by means of postmortem injection or by the benzidine stain. In a review of the literature, we found an interesting fact. Most of what has been written in the past forty years about the circulation of the human spinal cord, especially in anatomic and neurologic textbooks and handbooks, is either inaccurate or incomplete. A paper that gives an accurate and complete account is that by Kadyi, 1 published in 1889, a truly masterful piece of work. He pointed out that only one fourth of the nerve roots in man are accompanied by segmental arteries which contribute significantly to the circulation of the spinal cord; on the average there are but eight. The largest is one in the upper lumbar portion of the cord, the arteria radicalis anterior magna, first described by Adamkiewicz 2 in 1882.
Communication between neurons and astrocytes: relevance to the modulation of synaptic and network activity

Neuromodulation is a fundamental process in the brain that regulates synaptic transmission, neuronal network activity and behavior. Emerging evidence demonstrates that astrocytes, a major population of glial cells in the brain, play previously unrecognized functions in neuronal modulation. Astrocytes can detect the level of neuronal activity and release chemical transmitters to influence neuronal function. For example, recent findings show that astrocytes play crucial roles in the control of Hebbian plasticity, the regulation of neuronal excitability and the induction of homeostatic plasticity. This review discusses the importance of astrocyte‐to‐neuron signaling in different aspects of neuronal function from the activity of single synapses to that of neuronal networks.