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We observed that in isolated perfused rat kidneys, sphingosine-1-phosphate produces S1P(2) receptor-mediated vasoconstriction, and this response increased in kidneys of diabetic rats. These results suggest that the antagonists of S1P(2) receptor may have potential as drugs to control diabetes-induced vascular complications. [ABSTRACT FROM AUTHOR]

Background: TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer's disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear., Methods: The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer's Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions., Results: Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 230 ), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2 222 ) and ENST00000338469 (TREM2 219 ), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin., Conclusions: TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD., (© 2023. The Author(s).)

Background: The optimal endovascular treatment (EVT) technique for middle cerebral artery (MCA) M2 segment occlusions remains unknown. We aim to analyze whether reperfusion rate, procedure times, procedure-related complications, and clinical outcome differed between patients with isolated M2 occlusions who underwent stent-retriever (SR) alone versus combined SR and contact aspiration (CA) as a front-line EVT., Methods: Patients who underwent EVT for isolated MCA-M2 occlusion were recruited from the prospectively ongoing ROSSETTI registry. Patients were divided regarding the EVT approach into SR alone versus SR+CA and propensity score matching was used to achieve baseline balance. Demographic, procedural, safety, and clinical outcomes were compared between groups. Multivariable logistic regression analysis was performed to identify independent predictors of first-pass effect (FPE) and 90-day modified Rankin scale (mRS) 0-2., Results: 214 patients underwent EVT for M2 occlusion, 125 treated with SR alone and 89 with SR+CA. Propensity score matchnig analysis selected 134 matched patients. The rates of FPE (42% vs 40%, p=1.000) and 90-day mRS 0-2 (60% vs 51%, p=0.281) were comparable between groups. Patients treated with SR alone had lower need of rescue therapy (p=0.006), faster times to reperfusion (p<0.001), and lower procedure-related complications (p=0.031). Higher initial Alberta Stroke Program Early CT Score was an independent predictor of FPE. Age, baseline National Institutes of Health Stroke Scale score, and procedure duration were significant predictors of good clinical outcome at 3 months., Conclusions: As front-line modality in M2 occlusions, the SR alone approach results in similar rates of reperfusion and good clinical outcomes to combined SR+CA and might be advantageous due to faster reperfusion times and fewer adverse events., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Increased dietary intake of niacin has been correlated with reduced risk of Alzheimer's disease (AD). Niacin serves as a high-affinity ligand for the receptor HCAR2 (GPR109A). In the brain, HCAR2 is expressed selectively by microglia and is robustly induced by amyloid pathology in AD. The genetic inactivation of Hcar2 in 5xFAD mice, a model of AD, results in impairment of the microglial response to amyloid deposition, including deficits in gene expression, proliferation, envelopment of amyloid plaques, and uptake of amyloid-β (Aβ), ultimately leading to exacerbation of amyloid burden, neuronal loss, and cognitive deficits. In contrast, activation of HCAR2 with an FDA-approved formulation of niacin (Niaspan) in 5xFAD mice leads to reduced plaque burden and neuronal dystrophy, attenuation of neuronal loss, and rescue of working memory deficits. These data provide direct evidence that HCAR2 is required for an efficient and neuroprotective response of microglia to amyloid pathology. Administration of Niaspan potentiates the HCAR2-mediated microglial protective response and consequently attenuates amyloid-induced pathology, suggesting that its use may be a promising therapeutic approach to AD that specifically targets the neuroimmune response.

Lead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tropical dry forests (TDFs) experience a long dry season in which plant species are subject to several months of water deficit. However, TDFs maintain a diverse group of plant life forms, growth forms and leaf phenology, and it is not clear how they vary in their mechanisms for coping with seasonal drought. We studied seasonal changes in leaf water potential (Ψleaf), gas exchange, photochemical activity and functional traits in evergreen and drought-deciduous species from a TDF to determine if leaf phenology mediates plant responses to drought. We found seasonal decreases in Ψleaf, stomatal conductance (gs) and transpiration rate (E), and increases in both intrinsic and instantaneous water-use efficiency. We did not find seasonal differences in photosynthetic rate (Aarea) and carbon isotope composition (δ13C); however, these traits differed between leaf phenology groups, with drought-deciduous plants having higher Aarea and δ13C than evergreen plants. We also found that plants with high leaf nitrogen concentration (Narea) also had low mass-based photosynthetic rate (Amass), photosynthetic-nitrogen-use efficiency and specific leaf area, contrary to the expected relationships given by the leaf economics spectrum. Despite higher Narea, sclerophyllous leaves maintained lower Amass, and this increased structural toughness of leaves may be imposing a stronger limitation for CO2 diffusion and hence photosynthesis. Overall, we found more water-conservative traits in deciduous than in evergreen plants, contrary to what is known about these two leaf phenology groups in other seasonal sites both at tropical and temperate latitudes., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

Unlabelled: Oxidative stress has been associated with diabetic complications like nephropathies. Recent studies indicate that ursodeoxycholic acid (UDCA) may be beneficial preventing diabetes-induced oxidative stress and secondary complications. Thus, we study if the UDCA-treatment decreases the expression of sodium-glucose cotransporter (SGLT2) and the oxidative stress in the kidney of diabetic rats., Methods: The diabetes model was established by intraperitoneal injection of streptozotocin (50mg/kg). SGLT2 expression was evaluated by western blot and RT-PCR. Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase activities (SOD) and immunohistochemical analysis of 3-nitrotyrosine (3-NT)., Results: Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The SGLT2 expression and mRNA levels increased in cortex of kidney from diabetic rats. The CAT activity decreased in cortex and medulla from diabetic rats, otherwise the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The UDCA treatment was able to decrease hyperglycemia and prevents the SGLT2 over-expression, restores the CAT and GPX activities and decreases 3-NT staining., Conclusion: The UDCA treatment prevents the over-expression of SGLT2 and oxidative stress in kidney of diabetic rats., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to evaluate whether single-voxel (1)H MRS could add useful information to conventional MRI in the preoperative characterisation of the type and grade of brain tumours. MRI and MRS examinations from a prospective cohort of 40 consecutive patients were analysed double blind by radiologists and spectroscopists before the histological diagnosis was known. The spectroscopists had only the MR spectra, whereas the radiologists had both the MR images and basic clinical details (age, sex and presenting symptoms). Then, the radiologists and spectroscopists exchanged their predictions and re-evaluated their initial opinions, taking into account the new evidence. Spectroscopists used four different systems of analysis for (1)H MRS data, and the efficacy of each of these methods was also evaluated. Information extracted from (1)H MRS significantly improved the radiologists' MRI-based characterisation of grade IV tumours (glioblastomas, metastases, medulloblastomas and lymphomas) in the cohort [area under the curve (AUC) in the MRI re-evaluation 0.93 versus AUC in the MRI evaluation 0.85], and also of the less malignant glial tumours (AUC in the MRI re-evaluation 0.93 versus AUC in the MRI evaluation 0.81). One of the MRS analysis systems used, the INTERPRET (International Network for Pattern Recognition of Tumours Using Magnetic Resonance) decision support system, outperformed the others, as well as being better than the MRI evaluation for the characterisation of grade III astrocytomas. Thus, preoperative MRS data improve the radiologists' performance in diagnosing grade IV tumours and, for those of grade II-III, MRS data help them to recognise the glial lineage. Even in cases in which their diagnoses were not improved, the provision of MRS data to the radiologists had no negative influence on their predictions., (Copyright © 2011 John Wiley & Sons, Ltd.)

Unlabelled: The hyperglycemia triggers several chronic diabetic complications mediated by increased oxidative stress that eventually causes diabetic nephropathy. The aim of this study was to examine if the sodium-glucose cotransporter (SGLT2) inhibition prevents the oxidative stress in the kidney of diabetic rats., Methods: The diabetic rat model was established by intraperitoneal injection of streptozotocin (50 mg/kg). The inhibition of SGLT2 was induced by daily subcutaneous administration of phlorizin (0.4 g/kg). Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities and by immunohistochemical analysis of 3-nitrotyrosine (3-NT)., Results: Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The CAT activity decreased in cortex and medulla from diabetic rats; in contrast, the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The inhibition of SGLT2 decreased hyperglycemia. However, significant diuresis and glucosuria remain in diabetic rats. The phlorizin treatment restores the CAT and GPX activities and decreases 3-NT staining., Conclusion: The inhibition of SGLT2 by phlorizin prevents the hyperglycemia and oxidative stress in kidney of diabetic rats, suggesting a prooxidative mechanism related to SGLT2 activity.

Background and Aims: Calotropis procera and Calotropis gigantea, originally from warm parts of Africa and Asia, are now pan-tropical and in ecological terms considered an indicator of overgrazed, disturbed lands; they grow successfully in dry areas. Variations in water relations, morphology and photosynthesis of the two species growing in the same habitat were studied to assess possible mechanisms of tolerance to drought and how these relate to their ecophysiological success. Also the hypothesis that their photosynthetic rate (A) under drought would be affected by stomatal and non-stomatal limitations was tested., Methods: Water relations, gas exchange, water use efficiency (WUE), fluorescence parameters, pubescence and specific leaf area (SLA) of Calotropis procera and C. gigantea plants growing in the field were evaluated during the wet (WS) and dry (DS) seasons., Results: The xylem water potential (ψ) was similar in both species during the WS and DS; drought caused a 28 % decrease of ψ. In C. procera, A, stomatal conductance (g(s)) and carboxylation efficiency (CE) were higher in the WS with half the values of those during the DS, this species being more affected by drought than C. gigantea. A high δ(13)C of C. gigantea (-26·2 ‰) in the WS indicated a higher integrated WUE, in agreement with its lower g(s). Leaves of C. gigantea were more pubescent than C. procera. Relative stomatal and non-stomatal limitation of A increased with drought in both species; no changes in maximum quantum yield of photosystem II (PSII; F(v)/F(m)) were observed. The decrease in the relative quantum yield of PSII (ϕ(PSII)) and in the photochemical quenching coefficient (q(P)) was more pronounced in C. procera than in C. gigantea., Conclusions: The photosynthetic capacity of C. procera was higher than that of C. gigantea. During the DS, A was regulated by stomatal and non-stomatal factors in a coordinated manner and drought did not cause chronic photoinhibition. A higher density of trichomes and leaf angle in C. gigantea may contribute to the maintenance of A and confer more efficient protection of photochemical activity in the DS. Ecophysiological traits such as high photosynthetic rate throughout the year even during the DS, and high WUE, highly pubescent leaves and low SLA observed in both species contribute to the establishment and growth of Calotropis in dry conditions.

The present study evaluated whether enalaprilat (the active form of enalapril, an angiotensin-converting enzyme inhibitor) activates B(1) receptors. We observed that the levels of B(1) receptor mRNA and protein expression were upregulated in the kidneys of diabetic rats. Bradykinin (BK)-induced renal vasodilation decreased in isolated perfused kidneys of diabetic rats, but des-Arg(9)-BK-induced renal vasodilation increased. Enalaprilat also produced vasodilation in the isolated perfused kidneys of control and diabetic rats. The response to des-Arg(9)-BK or enalaprilat was blocked by Lys-(des-Arg(9), Leu(8))-BK (a B(1) receptor antagonist) and N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase). These results suggest that enalaprilat activates B(1) receptors and stimulates the production of nitric oxide in the kidneys of both control and diabetic rats., (Copyright © 2011 S. Karger AG, Basel.)

Objective: The increase of reactive oxygen species (ROS) in diabetes potentiates the vascular effects of phenylephrine through nitric oxide (NO) impairment, facilitating the development of diabetic nephropathy. We propose that the combination of an antioxidant and L-arginine as diet supplements could prevent the increased vascular response to phenylephrine in diabetic animals., Design: Changes in the adrenergic system play an important role in the development of vascular complications in the prediabetic condition. The vasoconstrictor effects of phenylephrine are regulated by NO, and the impairment of endothelium-dependent vasodilation in diabetes is associated with ROS., Setting: Diabetes was induced with a low dose (55 mg/kg body weight) of streptozotocin in 7-week-old rats. Diabetic rats were fed with a diet supplement containing a combination of vitamin E, vitamin C, eicosapentaenoic acid, docosahexaenoic acid, and L-arginine, and the effects on phenylephrine-induced renal vascular responses were evaluated., Results: Phenylephrine increased the renal perfusion pressure of isolated perfused kidneys from diabetic rats compared with nondiabetic rats. This effect was associated with reduced nitrite release as well as reduced plasma tetrahydrobiopterin and increased superoxide anions in the renal tissue. Diet supplementation with a combination of L-arginine and vitamins in diabetic rats partially prevented the generation of superoxide associated with recovery of the renal release of NO and decreased phenylephrine-induced vasoconstrictor effects, compared with untreated diabetic rats. However, the administration of L-arginine or vitamins alone did not affect phenylephrine-induced vasoconstriction. Vitamin treatment alone did decrease superoxide generation., Conclusion: The protective mechanism of NO on the vasoconstrictor effects of phenylephrine in the kidney is lost during the development of diabetes, probably via the actions of ROS through a decrease in tetrahydrobiopterin, thus contributing to the pathogenesis of diabetic nephropathy. Restoration of this protective NO mechanism can be achieved by simultaneously stimulating NO synthesis and preventing the effects of ROS through the use of L-arginine and a combination of vitamins E and C as diet supplementation.

Angiotensin (ANG) II can be associated with gene expression regulation. Thus we studied the possible role of ANG II in the regulation of AT(2) mRNA and protein expression. We utilized sham-operated renal ablation rats as well as renal ablation rats pretreated during the first 7 days of the development of renal damage with either the angiotensin-converting inhibitor ramipril, the AT(1) receptor antagonist losartan, or the AT(2) receptor antagonist PD-123319. Renal tissue was analyzed for histological changes and expression of AT(2) receptor mRNA (by RT-PCR) and protein (by immunohistochemistry). To explore the physiological role of AT(2) receptor overexpression in the development of renal damage, blood pressure, urinary protein excretion, and renal damage were evaluated. A time-dependent increase in the expression of AT(2) receptor mRNA and protein was observed at 7, 15, and 30 days after renal ablation. Because these effects were already evident at day 7, the effects of ramipril, losartan, or PD-123319 were tested at this time. The ramipril group and the PD-123319-pretreated group showed inhibition of AT(2) receptor expression, whereas the losartan-pretreated group showed a further increase in AT(2) receptor expression. Inhibition of the AT(2) receptor during renal ablation was associated with increased renal damage and a further increase in the blood pressure. This suggests that overexpression of AT(2) receptors after renal ablation is modulated by ANG II through its own AT(2) receptor and that functional expression of this effect may represent a counterregulatory mechanism to modulate the renal damage induced by renal ablation.