Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H: quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase / 中国天然药物

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD+), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.

Effects of exercise type and intensity on visfatin and the metabolic syndrome in obesity / Efectos del tipo de ejercicio y de la intensidad en la visfatina y el síndrome metabólico en la obesidad / Efeitos do tipo de exercício e da intensidade na visfatina e a síndrome metabólica na obesidade

ABSTRACT Objective: Visfatin may regulate a variety of physiological functions and it has great potential to significantly enhance our knowledge of the treatment of metabolic syndrome. Metabolic syndrome (MS) refers to metabolic abnormalities, such as abdominal obesity, dyslipidemia, high low-density cholesterol, high blood pressure and diabetes, and physical activity is an important factor for the management of MS. Therefore, the purpose of this study is to investigate the effects of visfatin on MS and MS risk factors through differences in aerobic exercise intensity and exercise type based on the premise of the same amount of exercise (energy expenditure of 400 kcal per day). Method: Thirty two obese, middle-aged women were randomly assigned to exercise intensity groups VO2max 50% (MAE, n=8) and VO2max 80% (VAE, n=8) and to type of exercise groups VO2max 50% + TRX (MARE, n=8) and VO2max 80% + TRX (VARE, n=8). The exercise program was performed 5 times a week. The data was analyzed using two-way repeated measures ANOVA and post-hoc tests within groups with LSD. Results: Body weight (p<.01 and p<.001) and % body fat (p<.05 and p<.01) significantly decreased in all groups and visfatin only increased significantly after exercise in the VARE group (p<.05). TG, glucose, and waist circumstance (p<.05, p<.01, and p<.001) significantly decreased in all groups and HDL-C (p<.05) only increased significantly after exercise only in the MARE group. Conclusion: These results suggest that, in spite of differences in exercise intensity and exercise type, exercise is effective in improving obesity and MS risk factors, but further research is needed on the exact mechanisms of visfatin. Level of evidence I; Therapeutic Studies Investigating the Results of Treatment .

RESUMEN Objetivo: La visfatina puede regular diversas funciones fisiológicas y tiene gran potencial para mejorar significativamente nuestro conocimiento sobre el tratamiento del síndrome metabólico. El síndrome metabólico (SM) se refiere a anormalidades metabólicas, como obesidad abdominal, dislipidemia, colesterol de baja densidad elevado, hipertensión y diabetes, siendo la actividad física un factor importante para el manejo del SM. Siendo así, el objetivo de este estudio es investigar los efectos de la visfatina sobre los factores de riesgo de SM por medio de diferencias de la intensidad de ejercicios aeróbicos y del tipo de ejercicio, con base en la premisa de misma cantidad de ejercicio (gasto energético de 400 kcal por día). Método: Treinta y dos mujeres obesas de media edad fueron aleatoriamente designadas para grupos de intensidad de ejercicio con VO2máx de 50% (EAM, n = 8) y VO2máx de 80% (EAV, n = 8) y grupos con VO2máx de 50% + ERC (EARM, n = 8) y VO2máx de 80% + ERC (EARV, n = 8). El programa de ejercicios fue realizado cinco veces por semana. Los datos fueron analizados con ANOVA de dos vías con medidas repetidas y tests post-hoc en los grupos con DMS. Resultados: El peso corporal (p < 0,01 y p < 0,001) y porcentual de grasa corporal (p < 0,05 y p < 0,01) disminuyeron significativamente en todos los grupos y la visfatina sólo aumentó significativamente después del ejercicio en el grupo EARV (p < 0,05). Los triglicéridos, la glucosa y la circunferencia de la cintura (p < 0,05, p < 0,01 e p < 0,001) disminuyeron significativamente en todos los grupos y el HDL-C (p < 0,05) sólo aumentó significativamente después del ejercicio sólo en el grupo EARM. Conclusión: Esos resultados sugieren que, a pesar de las diferencias de intensidad y tipo de los ejercicios, los mismos son eficaces para mejorar la obesidad y los factores de riesgo del SM, por ende, son necesarias más investigaciones sobre los mecanismos exactos de la visfatina. Nivel de Evidencia I; Estudios terapéuticos - Investigación de los resultados del tratamiento .

RESUMO Objetivo: A visfatina pode regular diversas funções fisiológicas e tem grande potencial para aprimorar significativamente nosso conhecimento sobre o tratamento da síndrome metabólica. A síndrome metabólica (SM) refere-se a anormalidades metabólicas, como obesidade abdominal, dislipidemia, colesterol de baixa densidade elevado, hipertensão e diabetes, sendo a atividade física um fator importante para o manejo da SM. Assim sendo, o objetivo deste estudo é investigar os efeitos da visfatina sobre os fatores de risco de SM por meio de diferenças da intensidade de exercícios aeróbicos e do tipo de exercício, com base na premissa de mesma quantidade de exercício (gasto energético de 400 kcal por dia). Método: Trinta e duas mulheres obesas de meia-idade foram randomicamente designadas para grupos de intensidade de exercício com VO2máxde 50% (EAM, n = 8) e VO2máxde 80% (EAV, n = 8) e grupos com VO2máxde 50% + ERC (EARM, n = 8) e VO2máxde 80% + ERC (EARV, n = 8). O programa de exercícios foi realizado 5 vezes por semana. Os dados foram analisados com ANOVA de duas vias com medidas repetidas e testes post-hoc nos grupos com DMS. Resultados: O peso corporal (p < 0,01 e p < 0,001) e percentual de gordura corporal (p < 0,05 e p < 0,01) diminuíram significativamente em todos os grupos e a visfatina só aumentou significativamente depois do exercício no grupo EARV (p < 0,05). Triglicérides, glicose e circunferência da cintura (p < 0,05, p < 0,01 e p < 0,001) diminuíram significativamente em todos os grupos e o HDL-C (p < 0,05) só aumentou significativamente depois o exercício apenas no grupo EARM. Conclusão: Esses resultados sugerem que, apesar das diferenças de intensidade e tipo dos exercícios, eles são eficazes para melhorar a obesidade e os fatores de risco da SM, porém, são necessárias mais pesquisas sobre os mecanismos exatos da visfatina. Nível de Evidência I; Estudos terapêuticos - Investigação dos resultados do tratamento .

Effect of curcumin on visfatin and zinc-α2-glycoprotein in a rat model of non-alcoholic fatty liver disease

ABSTRACT PURPOSE: To investigate the effect of curcumin on visfatin and zinc-α2-glycoprotein (ZAG) expression levels in rats with non-alcoholic fatty liver disease (NAFLD). METHODS: Fifty-six male rats were randomly divided into a control group (n=16) and model group (n=40) and were fed on a normal diet or a high-fat diet, respectively. Equal volumes of sodium carboxymethyl cellulose (CMC) were intragastrically administered to the control group for 4 weeks. At the end of the 12th week, visfatin and ZAG protein expression levels were examined by immunohistochemistry. Visfatin mRNA levels were measured by semi-quantitative reverse transcription polymerase chain reaction. RESULTS: Compared with the control group, the model group showed significantly increased expression of visfatin in liver tissue (P < 0.01) and significantly decreased expression of ZAG (P < 0.01). These effects were ameliorated by curcumin treatment. CONCLUSIONS: Visfatin and zinc-α2-glycoprotein may be involved in the pathogenesis of NAFLD. Treatment of NAFLD in rats by curcumin may be mediated by the decrease of visfatin and the increase of non-alcoholic fatty liver disease.

Distribution and expression of visfatin-positive cells in the spleen of lipopolysaccharide-stimulated piglets / Distribución y expresión de células visfatin positivas en el bazo de lechones estimulados con lipopolisacáridos

The histological changes in the spleen and the immunohistochemical expression of visfatin in lipopolysaccharide-stimulated piglets are reported to examine the relation between visfatin and inflammation. The results are as follows: (1) After LPS treated, the spleen displayed thicker capsules and trabecula, the thinner periarterial lymphatic sheath, and the more expandable splenic sinusoid, with an increase in the number of splenic nodules, lymphocytes, ellipsoids of the marginal zone, red blood cells and macrophagocytes. (2) Visfatin-positive cells were mainly distributed in the red pulp of the spleen, with less in splenic nodules and periarterial lymphatic sheath. In the LPS-treated group, the signal intensity and quantity of the visfatin-positive cells were significantly higher in the red pulp and the ellipsoids of the spleen (P<0.01), whereas lower in the periarterial lymphatic sheath. These results indicate that LPS stimulation induces inflammation, causing the histological changes of the piglet spleen and activating humoral immune response. Moreover, variation of visfatin in the spleen suggests that lymphocytes and macrophages are the potent source of visfatin which participates in the humoral immune response in the inflammation.

Se presentan los cambios histológicos en el bazo y la expresión inmunohistoquímica de visfatin en lechones estimulados mediante lipopolisacáridos (LPS) con el objetivo de estudiar la relación entre visfatin e inflamación. Los resultados fueron los siguientes: (1) Después del tratamiento por LPS se observaron en el bazo cápsulas más gruesas y trabéculas, una vaina linfática periarterial más delgada, y más sinusoides esplénicos expandible, con un aumento en el número de nódulos esplénicos, linfocitos, elipsoides de la zona marginal, como también un aumento de las células rojas de la sangre y los macrofagocitos. (2) Las células visfatina-positivas se distribuyeron principalmente en la pulpa roja del bazo, con una cantidad menor en los nódulos esplénicos y la vaina linfática periarterial. En el grupo tratado con LPS, la intensidad de la señal y número de células positivas fueron significativamente mayor en la pulpa roja y los elipsoides del bazo (P<0,01), mientras que estas fueron menores en la vaina linfática periarterial. Estos resultados indican que la estimulación con LPS induce la inflamación provocando cambios histológicos del bazo de los lechones y la activación de la respuesta inmune humoral. Por otra parte, la variación de visfatin en el bazo sugiere que los linfocitos y los macrófagos son una fuente potente de visfatin en la respuesta inmune humoral de la inflamación.

New concepts in white adipose tissue physiology

Numerous studies address the physiology of adipose tissue (AT). The interest surrounding the physiology of AT is primarily the result of the epidemic outburst of obesity in various contemporary societies. Briefly, the two primary metabolic activities of white AT include lipogenesis and lipolysis. Throughout the last two decades, a new model of AT physiology has emerged. Although AT was considered to be primarily an abundant energy source, it is currently considered to be a prolific producer of biologically active substances, and, consequently, is now recognized as an endocrine organ. In addition to leptin, other biologically active substances secreted by AT, generally classified as cytokines, include adiponectin, interleukin-6, tumor necrosis factor-alpha, resistin, vaspin, visfatin, and many others now collectively referred to as adipokines. The secretion of such biologically active substances by AT indicates its importance as a metabolic regulator. Cell turnover of AT has also recently been investigated in terms of its biological role in adipogenesis. Consequently, the objective of this review is to provide a comprehensive critical review of the current literature concerning the metabolic (lipolysis, lipogenesis) and endocrine actions of AT.

Impact of metformin treatment and swimming exercise on visfatin levels in high-fat-induced obesity rats / Impacto do tratamento com metformina e da natação nos níveis de visfatina em ratos com obesidade induzida por dieta com alto teor de gordura

Objective : Visfatin is a recently discovered adipocytokine that contributes to glucose and obesity-related conditions. Until now, its responses to the insulin-sensitizing agent metformin and to exercise are largely unknown. We aim to investigate the impact of metformin treatment and/or swimming exercise on serum visfatin and visfatin levels in subcutaneous adipose tissue (SAT), peri-renal adipose tissue (PAT) and skeletal muscle (SM) of high-fat-induced obesity rats. Materials and methods : Sprague-Dawley rats were fed a normal diet or a high-fat diet for 16 weeks to develop obesity model. The high-fat-induced obesity model rats were then randomized to metformin (MET), swimming exercise (SWI), or adjunctive therapy of metformin and swimming exercise (MAS), besides high-fat obesity control group and a normal control group, all with 10 rats per group. Zoometric and glycemic parameters, lipid profile, and serum visfatin levels were assessed at baseline and after 6 weeks of therapy. Visfatin levels in SAT, PAT and SM were determined by Western Blot. Results : Metformin and swimming exercise improved lipid profile, and increased insulin sensitivity and body weight reduction were observed. Both metformin and swimming exercise down-regulated visfatin levels in SAT and PAT, while the adjunctive therapy conferred greater benefits, but no changes of visfatin levels were observed in SM. Conclusion : Our results indicate that visfatin down-regulation in SAT and PAT may be one of the mechanisms by which metformin and swimming exercise inhibit obesity. .

Objetivo : A visfatina é uma adipocina recentemente descoberta que contribui com as condições relacionadas à glicose e à obesidade. Até hoje, pouco se sabe da sua resposta à metformina, um agente sensibilizador de insulina, e ao exercício. Nosso objetivo foi investigar o impacto do tratamento com metformina e/ou da natação sobre a visfatina no soro e no tecido adiposo subcutâneo (TAS), tecido adiposo perirrenal (TAP) e músculo esquelético (ME) em ratos com obesidade induzida por dieta com alto teor de gordura. Materiais e métodos : Ratos Sprague-Dawley foram alimentados com uma dieta normal ou com alto teor de gordura por 16 semanas para o desenvolvimento de um modelo de obesidade. Os ratos do modelo de obesidade foram, então, randomizados para a metformina, natação ou terapia de combinação com metformina e natação, além do grupo controle de obesidade induzida por alto teor de gordura e do grupo controle normal. Cada grupo apresentava 10 ratos. Parâmetros zoométricos e glicêmicos, perfil lipídico e níveis de visfatina sérica foram avaliados no momento inicial e após seis semanas de tratamento. Os níveis de visfatina em TAS, TAP e ME foram determinados por Western Blot. Resultados : A metformina e a natação melhoraram o perfil lipídico e aumentaram a sensibilidade à insulina, com redução do peso corporal. Tanto a metformina quanto a natação levaram à regulação para baixo dos níveis de visfatina no TAS e TAP, enquanto a terapia de combinação apresentou os maiores benefícios, mas não foram observadas alterações nos níveis de visfatina no ME. Conclusão : Nossos resultados indicam que a regulação para baixo da visfatina no TAS e TAP pode ser um dos mecanismos pelos quais a metformina ...