Mutations in the X‐linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain‐derived neurotrophic factor (BDNF) levels, but non‐specific overexpression of BDNF only partially improves the phenotype of Mecp2‐deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF‐containing vesicles, and is under‐expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho‐mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice—even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.
Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain-derived neurotrophic factor (BDNF) levels, but non-specific overexpression of BDNF only partially improves the phenotype of Mecp2-deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho-mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice-even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.
Breast and prostate cancers are frequently treated with chemotherapy. Several novel chemicals are being reported for this purpose, particularly synthetic and natural benzophenones. This work reports the synthesis of substituted 2‐hydroxybenzophenones through 1,4‐conjugate addition/intramolecular cycloaddition/dehydration of nitromethane on key intermediate chromones. Structures were extensively studied by means of 2D NMR spectroscopy and single‐crystal XRD. Their cytotoxicity was evaluated in vitro in two breast cancer cell lines (MDA‐MB‐231 and T47‐D) and one prostate cancer cell line (PC3). The most potent compound exhibited good cytotoxic effects against the three cancer cell lines (IC50 values ranging from 12.09 to 26.49 μm) and induced cell‐cycle retardation only on prostate cancer cells, which suggested that it might exert cell‐type‐specific effects.
Interneurons play a signi cant role in the functional organization of the striatum and some of them display marked plastic changes in dopamine-depleted conditions. Here, we applied immunohistochemistry on brain sections from 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease and sham animals to characterize the regional distribution and the morphological and neurochemical changes of striatal interneurons expressing the calcium binding protein calretinin (CR). Two morphological subtypes of calretinin-immunostained (CR+) interneurons referred respectively as small and medium-sized CR+ interneurons were detected in 6-OHDA and sham-lesioned animals. The small cells (9-12 µm) prevail in the anterior and dorsal striatal regions; they stain intensely for CR and display a single slightly varicose and moderately arborized process. The medium-sized CR+ interneurons (15-20 µm) are slightly more numerous than the small CR+ cells and rather uniformly distributed within the striatum; they stain weakly for CR and display 2-3 long, slightly varicose and poorly branched dendrites. The density of medium CR+ interneurons is signi cantly decreased in the dopamine-depleted striatum (158 ± 15 neurons/mm 3 ), when compared to sham animals (370 ± 41 neurons/mm 3 ), whereas that of the small-sized CR+ interneurons is unchanged (174 ± 46 neurons/mm 3 in 6-OHDA-lesioned striatum and 164 ± 22 neurons/mm 3 in sham-lesioned striatum). The nucleus accumbens is populated only by medium-sized CR+ interneurons, which are distributed equally among the core and shell compartments and whose density is unaltered after dopamine denervation. Our results provide the rst evidence that the medium-sized striatal interneurons expressing low level of CR are speci cally targeted by dopamine denervation, while the small and intensely immunoreactive CR+ cells remain unaffected.These ndings suggest that high expression of the calcium binding protein CR might protect striatal interneurons against an increase in intracellular calcium level that is believed to arise from altered glutamate corticostriatal transmission in Parkinson's disease.in ammatory cytokines and reduced concentrations of neurotrophic factors have previously been reported in the 6-OHDA-lesioned mice (Antunes et al. 2020).
Показано, что при введении цитрата крысам с экспериментальным токсическим гепатитом происходит снижение параметров биохемилюминесценции и содержания диеновых конъюгатов, возрастающих в условиях CCl 4 -индуцированного поражения печени. При этом активность аконитазы, снижающаяся при данной патологии, увеличивается. Активность супероксиддисмутазы и каталазы, увеличивающихся при экспериментальном токсическом гепатите, при введении цитрата также изменяются в сторону контрольных значений.Ключевые слова: крысы, токсический гепатит, цитрат, свободнорадикальные процессы, супероксиддисмутаза, каталаза.ВВЕДЕНИЕ. Согласно имеющимся в настоящее время данным, свободнорадикальное окисление (СРО), являющееся необходимым этапом различных процессов жизнедеятельности, при чрезмерной интенсификации служит одним из ведущих механизмов клеточной патологии, включая аутоиммунные болезни, хронические воспаления, сердечно-сосудистые, нейродегенеративные заболевания, болезни печени и другие [1][2][3][4]. Основную роль в интенсификации СРО играют усиление генерации активных форм кислорода (АФК) и повышение содержания прооксидантов -ионов Fe 2+ , высвобождающихся из вне-и внутриклеточных депо [5]. В связи с распространённостью и тяжестью свободнорадикальных патологий значительный интерес представляет исследование эндогенных факторов, обладающих антиоксидантным потенциалом и способных оказывать протекторный эффект при развитии заболеваний подобного рода. Цитрат -один из важнейших метаболитов в организме млекопитающих, интермедиат цикла трикарбоновых кислот, регулятор ключевых ферментов гликолиза, биосинтеза жирных кислот, -способен проявлять антиоксидантные свойства благодаря наличию диссоциирующих карбоксильных групп, что позволяет ему хелатировать ионы Fe 2+ и Са 2+. Показано, что при взаимодействии комплекса "цитрат-Fe 2+
Interneurons play a significant role in the functional organization of the striatum and some of them display marked plastic changes in dopamine-depleted conditions. Here, we applied immunohistochemistry on brain sections from 6-hydroxydopamine (6-OHDA) mouse model of Parkinson’s disease and sham animals to characterize the regional distribution and the morphological and neurochemical changes of striatal interneurons expressing the calcium binding protein calretinin (CR). Two morphological subtypes of calretinin-immunostained (CR+) interneurons referred respectively as small and medium-sized CR+ interneurons were detected in 6-OHDA and sham-lesioned animals. The small cells (9-12 µm) prevail in the anterior and dorsal striatal regions; they stain intensely for CR and display a single slightly varicose and moderately arborized process. The medium-sized CR+ interneurons (15-20 µm) are slightly more numerous than the small CR+ cells and rather uniformly distributed within the striatum; they stain weakly for CR and display 2-3 long, slightly varicose and poorly branched dendrites. The density of medium CR+ interneurons is significantly decreased in the dopamine-depleted striatum (158 ± 15 neurons/mm3), when compared to sham animals (370 ± 41 neurons/mm3), whereas that of the small-sized CR+ interneurons is unchanged (174 ± 46 neurons/mm3 in 6-OHDA-lesioned striatum and 164 ± 22 neurons/mm3 in sham-lesioned striatum). The nucleus accumbens is populated only by medium-sized CR+ interneurons, which are distributed equally among the core and shell compartments and whose density is unaltered after dopamine denervation. Our results provide the first evidence that the medium-sized striatal interneurons expressing low level of CR are specifically targeted by dopamine denervation, while the small and intensely immunoreactive CR+ cells remain unaffected. These findings suggest that high expression of the calcium binding protein CR might protect striatal interneurons against an increase in intracellular calcium level that is believed to arise from altered glutamate corticostriatal transmission in Parkinson’s disease.
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