Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases

Dietary Calcium but Not Elemental Calcium from Supplements Is Associated with Body Composition and Obesity in Chinese Women

We assessed whether dietary calcium intake or calcium supplements associated with body composition and obesity in a Chinese population.A cross-sectional survey was performed in a population of 8940, aged 20 to 74 y. 8127 participants responded (90.9%). Height, weight, fat mass (FM), waist circumference (WC) and hip circumference were measured. Obesity definition: body mass index (BMI) ≥28 kg/m(2) (overall obesity); WC ≥85 cm for men or ≥80 cm for women (abdominal obesity І) and waist hip ratio (WHR) ≥0.90 for men or ≥0.85 for women (abdominal obesity П). The data on dietary calcium and calcium supplements were collected using food-frequency questionnaire and self-report questionnaire. Multivariate linear and multivariable logistic regressions were used to examine the associations between dietary calcium intake or calcium supplements and body composition and obesity.The average dietary calcium intake of all subjects was 430 mg/d. After adjusting for potential confounding factors, among women only, negative associations were observed between habitual dietary calcium intake and four measures of body composition (β, -0.086, P<0.001 for BMI; β, -0.072, P<0.001 for WC; β, -0.044, P<0.05 for WHR; and β, -0.058, P<0.01 for FM, respectively) and both measures of abdominal obesity (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI], 0.80-0.93; P<0.001, for abdominal obesity I; OR = 0.92, 95% CI, 0.86-0.99; P = 0.026, for abdominal obesity II). These associations were not observed among men (P>0.05). Similarly, among both men and women, we did not observe significant associations between calcium supplements and any measures of body composition or abdominal obesity (P>0.05).Dietary calcium from food rather than elemental calcium from calcium supplements has beneficial effects on the maintenance of body composition and preventing abdominal obesity in Chinese women

Bioactivities of EF24, a Novel Curcumin Analog: A Review

Curcumin is an attractive agent due to its multiple bioactivities. However, the low oral bioavailability and efficacy profile hinders its clinical application. To improve the bioavailability, many analogs of curcumin have been developed, among which EF24 is an excellent representative. EF24 has enhanced bioavailability over curcumin and shows more potent bioactivity, including anti-cancer, anti-inflammatory, and anti-bacterial. EF24 inhibits tumor growth by inducing cell cycle arrest and apoptosis, mainly through its inhibitory effect on the nuclear factor kappa B (NF-κB) pathway and by regulating key genes through microRNA (miRNA) or the proteosomal pathway. Based on the current structure, more potent EF24 analogs have been designed and synthesized. However, some roles of EF24 remain unclear, such as whether it induces or inhibits reactive oxygen species (ROS) production and whether it stimulates or inhibits the mitogen activated kinase-like protein (MAPK) pathway. This review summarizes the known biological and pharmacological activities and mechanisms of action of EF24

Effects of acute administration of different doses of methylphenidate on cognition in healthy young

Os chamados ampliadores cognitivos têm sido ampla e crescentemente utilizados por indivíduos saudáveis, que apesar de não apresentarem nenhum tipo de patologia, buscam por melhoras no desempenho cognitivo. Um fármaco utilizado para este fim é o metilfenidato, droga de primeira escolha para tratamento do transtorno de déficit de atenção e hiperatividade (TDAH). O presente estudo visou verificar o efeito da administração aguda de diferentes doses de metilfenidato (10, 20 e 40 mg e placebo) sobre uma ampla gama de funções cognitivas em jovens saudáveis. Participaram do estudo 36 jovens universitários ou graduados, tendo sido realizados testes de atenção, memória operacional, episódica e semântica. Não foram observadas diferenças no desempenho dos sujeitos em nenhum dos testes. Houve efeito na auto-avaliação de bem estar, sendo este efeito dose dependente – 40 mg > placebo. De acordo com a literatura recente, medicações psicoestimulantes, como o metilfenidato, produzem melhoras no desempenho quando os processos cognitivos estão abaixo de um nível ótimo o que não era o caso dos sujeitos do presente estudo. Sendo assim, a impressão que o metilfenidato melhora o desempenho cognitivo em pessoas jovens e saudáveis se deve provavelmente ao efeito subjetivo de bem estar.The so called cognitive enhancers have been widely and increasingly used by healthy individuals, who despite not having any kind of pathology, seek improvements in cognitive performance. A drug used for this purpose is methylphenidate, a first choice drug for the treatment of the attention deficit and hyperactivity disorder (ADHD). This study aimed to evaluate the effect of acute administration of different doses of methylphenidate (10, 20 and 40 mg and placebo) in a wide range of cognitive functions in healthy young subjects. Participated in the study 36 university students or graduates, and were applied tests of attention, working memory, episodic and semantic memory. There were no differences among the groups in any of the tests. Significant effect on self-assessment of well being was observed, and this effect was dose dependent - 40 mg> placebo. According to recent literature, psychostimulant medications such as methylphenidate, produce improvements in performance when cognitive processes are below an optimal level which was not the case of the subjects of this study. Thus, the impression that methylphenidate improves cognitive performance in healthy young people is probably due to the effect of subjective well-being.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Associação Fundo de Incentivo à Psicofarmacologia (AFIP)BV UNIFESP: Teses e dissertaçõe

Glycine in the prevention of neonatal necrotizing enterocolitis lesions: experimental study in rats

Objetivo: Avaliar o efeito da glicina no intestino e em órgãos à distância num modelo experimental de enterocolite necrosante neonatal em ratos recém-nascidos. Métodos: Foram utilizados ratos Wistar recém-nascidos distribuídos em três grupos: G1: controle, G2: animais submetidos a hipóxia-reoxigenação (H-R), G3: animais submetidos a hipóxia-reoxigenação após uma infusão intraperitoneal de glicina 5%.Segmentos intestinais foram preparados para análise histológica, imunohistoquímica com caspase 3 clivada e lamina A clivada, como marcadores para apoptose e dosagem tecidual de Malondialdeído (MDA). O fígado foi preparado para avaliação imunohistoquímica e dosagem de malondialdeído tecidual, e os rins foram preparados para avaliação imunohistoquímica. Resultados: A dosagem de MDA tecidual mostrou que o grupo de animais submetido a H-R apresentou valores maiores do que o grupo previamente submetido à injeção intraperitoneal de glicina (p < 0,05). O índice apoptótico pela avaliação da caspase 3 clivada e lamina A clivada foi maior nos animais submetidos à H-R do que nos animais que receberam previamente glicina em todos os órgãos examinados, porém nos rins a avaliação pela lamina A clivada não foi significante, quando da avaliação estatística. A análise histológica não mostrou diferença estatística entre o grupo H-R e o previamente submetido à injeção de glicina. Conclusões: A glicina foi capaz de reduzir os efeitos deletérios da hipóxiareoxigenação, quando se considerou como critério de avaliação a dosagem de MDA e os índices de apoptose celular e não influenciou, estatisticamente, as alterações histológicas.Objective: To evaluate the effect of glycine on the intestine and in distant organs, in an experimental model of neonatal necrotizing enterocolitis in rats. Methods: Newborn Wistar rats were utilized, distributed into three groups: G1: control, G2: animals subjected to hypoxia-reoxygenation (H-R), G3: animals subjected to hypoxia-reoxygenation after intraperitoneal infusion of 5% glycine. Intestinal segments were prepared for histological analysis, immunohistochemistry using cleaved caspase-3 and cleaved lamina-A as markers for apoptosis, and tissue assaying for malonaldehyde (MDA). The liver and kidneys were prepared for immunohistochemical evaluation and the liver alone for tissue MDA assaying. Results: Tissue MDA assaying showed that the animals subjected to H-R alone presented higher values than did those previously subjected to glycine infusion (p < 0.05). The apoptosis index from evaluation of cleaved caspase-3 and cleaved lamina-A was greater in the animals subjected to H-R alone than in those previously subjected to glycine infusion, in all the organs examined. However, in the kidneys the findings from cleaved lamina-A did not present any statistical difference. The histological analysis did not show any statistical difference between the group with H-R alone and the group previously subjected to glycine infusion. Conclusions: Glycine was capable of reducing the deleterious effects from hypoxiareoxygenation, when the MDA assay and cell apoptosis index were considered as the evaluation criteria.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)BV UNIFESP: Teses e dissertaçõe

OsPIE1, the Rice Ortholog of Arabidopsis PHOTOPERIOD-INDEPENDENT EARLY FLOWERING1, Is Essential for Embryo Development

orthologs in monocots remains unknown., respectively).Taken together, our results suggest that OsPIE1 is the rice ortholog of Arabidopsis PIE1 and plays an essential role in rice embryo development

The Cross Talk between Cellular Senescence and Melanoma: From Molecular Pathogenesis to Target Therapies

Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of melanoma, which can induce reactive oxygen species (ROS) production and the presence of DNA damage in the cells, and results in cell senescence. As cellular senescence plays an important role in the relationship that exists between the skin aging process and the development of melanoma, the present study provides insight into the literature concerning the topic at present and discusses the relationship between skin aging and melanoma, including the mechanisms of cellular senescence that drive melanoma progression, the microenvironment in relation to skin aging and melanoma factors, and the therapeutics concerning melanoma. This review focuses on defining the role of cellular senescence in the process of melanoma carcinogenesis and discusses the targeting of senescent cells through therapeutic approaches, highlighting the areas that require more extensive research in the field