Search Results (6)

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (−3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy. Full article

Polyphenols are an important family of molecules of vegetal origin present in many medicinal and edible plants, which represent important alimentary sources in the human diet. Polyphenols are known for their beneficial health effects and have been investigated for their potential protective role against various pathologies, including cancer, brain dysfunctions, cardiovascular diseases and stroke. The prevention of stroke promoted by polyphenols relies mainly on their effect on cardio- and cerebrovascular systems. However, a growing body of evidence from preclinical models of stroke points out a neuroprotective role of these molecules. Notably, in many preclinical studies, the polyphenolic compounds were effective also when administered after the stroke onset, suggesting their possible use in promoting recovery of patients suffering from stroke. Here, we review the effects of the major polyphenols in cellular and in vivo models of both ischemic and hemorrhagic stroke in immature and adult brains. The results from human studies are also reported. Full article

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain–blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators. Full article

Bioactive components, due in part to their epigenetic properties, are beneficial for preventing several human diseases including cerebrovascular pathologies. However, no clear demonstration supports the idea that these molecules still conserve their epigenetic effects when acting at very low concentrations reproducing the brain levels achieved after oral administration of a micronutrient supplement. In the present study, we used a cellular model of brain ischemia to investigate the neuroprotective and epigenetic activities of a commercially available micronutrient mixture (polyphenol-enriched micronutrient mixture, PMM) enriched in polyphenols ((-)-epigallocatechin-3-gallate, quercetin, resveratrol), α-lipoic acid, vitamins, amino acids and other micronutrients. Mimicking the suggested dietary supplementation, primary cultures of mouse cortical neurons were pre-treated with PMM and then subjected to oxygen glucose deprivation (OGD). Pre-treatment with PMM amounts to provide bioactive components in the medium in the nanomolar range potently prevented neuronal cell death. The protection was associated with the deacetylation of the lysin 310 (K310) on NF-κB/RelA as well as the deacetylation of H3 histones at the promoter of Bim, a pro-apoptotic target of ac-RelA(K310) in brain ischemia. Epigenetic regulators known to shape the acetylation state of ac-RelA(K310) moiety are the histone acetyl transferase CBP/p300 and the class III histone deacetylase sirtuin-1. In view of that evidence, the protection we here report unveils the efficacy of bioactive components endowed with either inhibitory activity on CBP/p300 or stimulating activity on the AMP-activated protein kinase–sirtuin 1 pathway. Our results support a potential synergistic effect of micronutrients in the PMM, suggesting that the intake of a polyphenol-based micronutrient mixture can reduce neuronal vulnerability to stressful conditions at concentrations compatible with the predicted brain levels reached by a single constituent after an oral dose of PMM. Full article

Histone deacetylation, together with altered acetylation of NF-κB/RelA, encompassing the K310 residue acetylation, occur during brain ischemia. By restoring the normal acetylation condition, we previously reported that sub-threshold doses of resveratrol and entinostat (MS-275), respectively, an activator of the AMP-activated kinase (AMPK)-sirtuin 1 pathway and an inhibitor of class I histone deacetylases (HDACs), synergistically elicited neuroprotection in a mouse model of ischemic stroke. To improve the translational power of this approach, we investigated the efficacy of MS-275 replacement with valproate, the antiepileptic drug also reported to be a class I HDAC blocker. In cortical neurons previously exposed to oxygen glucose deprivation (OGD), valproate elicited neuroprotection at 100 nmol/mL concentration when used alone and at 1 nmol/mL concentration when associated with resveratrol (3 nmol/mL). Resveratrol and valproate restored the acetylation of histone H3 (K9/18), and they reduced the RelA(K310) acetylation and the Bim level in neurons exposed to OGD. Chromatin immunoprecipitation analysis showed that the synergistic drug association impaired the RelA binding to the Bim promoter, as well as the promoter-specific H3 (K9/18) acetylation. In mice subjected to 60 min of middle cerebral artery occlusion (MCAO), the association of resveratrol 680 µg/kg and valproate 200 µg/kg significantly reduced the infarct volume as well as the neurological deficits. The present study suggests that valproate and resveratrol may represent a promising ready-to-use strategy to treat post-ischemic brain damage. Full article

CSP-1103 (formerly CHF5074) has been shown to reverse memory impairment and reduce amyloid plaque as well as inflammatory microglia activation in preclinical models of Alzheimer’s disease. Moreover, it was found to improve cognition and reduce brain inflammation in patients with mild cognitive impairment. Recent evidence suggests that CSP-1103 acts through a single molecular target, the amyloid precursor protein intracellular domain (AICD), a transcriptional regulator implicated in inflammation and apoptosis. We here tested the possible anti-apoptotic and neuroprotective activity of CSP-1103 in a cell-based model of post-ischemic injury, wherein the primary mouse cortical neurons were exposed to oxygen-glucose deprivation (OGD). When added after OGD, CSP-1103 prevented the apoptosis cascade by reducing cytochrome c release and caspase-3 activation and the secondary necrosis. Additionally, CSP-1103 limited earlier activation of p38 and nuclear factor κB (NF-κB) pathways. These results demonstrate that CSP-1103 is neuroprotective in a model of post-ischemic brain injury and provide further mechanistic insights as regards its ability to reduce apoptosis and potential production of pro-inflammatory cytokines. In conclusion, these findings suggest a potential use of CSP-1103 for the treatment of brain ischemia. Full article