Synthesis and evaluation of novel N1-acylated 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors.

Protein kinase dysregulation was strongly linked to cancer pathogenesis. Moreover, histone alterations were found to be among the most important post-translational modifications that could contribute to cancer growth and development. In this context, haspin, an atypical serine/threonine kinase, phosphorylates histone H3 at threonine-3 and is notably overexpressed in various common cancer types. Herein, we report novel 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors. Amide coupling at N1 of the indazole ring with m-hydroxyphenyl acetic acid yielded compound 21 with an IC50 value of 78 nM against haspin. This compound showed a meaningful selectivity over 15 of the most common off-targets, including Clk 1-3 and Dyrk1A, 1B, and 2. The most potent haspin inhibitors 5 and 21 effectively inhibited the growth of the NCI-60 cancer cell lines, further emphasizing the success of our scaffold as a new selective lead for the development of anti-cancer therapeutic agents.

Failure of subcutaneous lipectomy to combat metabolic dysregulations in ovariectomy-induced obesity in young female rats.

PURPOSE: The deleterious effect of visceral adipose tissue accumulation is well known. However, the recent trend in liposuction is mal-directed toward easily accessible subcutaneous fat for the purpose of body shaping. The aim of the present study is to probe the metabolic effects of subcutaneous abdominal adipose tissue lipectomy in ovariectomized obese rats as well as the role of adipokines in these changes. METHODS: The study was conducted on young female rats randomized into two main groups according to the duration of the experiment, namely, 5-week and 10-week. Both groups were subdivided as follows: sham-operated, ovariectomized, and ovariectomized lipectomized rat groups. The rats underwent measurement of body weight (BW) and determination of body mass index (BMI). Fasting blood glucose, lipid profile, liver function, plasma malondialdehyde, leptin, and adiponectin were estimated, and the content of both blood and hepatic tissue of reduced glutathione was assessed. In addition, histological study of the liver, aorta, and perirenal fat of all rat groups was performed. RESULTS: Ovariectomy-induced obesity is marked by a significant increase in BW and BMI. Following subcutaneous lipectomy, the rats exhibited significant weight gain accompanied by fasting hyperglycemia, dyslipidemia, deterioration of synthetic function of the liver, and disturbed oxidant/antioxidant status. Histological examination revealed fatty infiltration of aortic and hepatic tissues. CONCLUSION: Despite the immediate positive effect of subcutaneous lipectomy for weight loss and/or body shaping, multiple delayed hazards follow the procedure, which should be carefully considered.

Novel approach for pathogenesis of osteoporosis in ovariectomized rats as a model of postmenopausal osteoporosis.

BACKGROUND: Obesity and osteoporosis are two chronic conditions that have been increasing in prevalence. Menopausal transition years place women at high risk for visceral obesity as well as osteoporosis. This study was carried out to elucidate the effect of visceral adiposity on ovariectomy-induced osteoporosis in rats. METHODS: We studied female Wistar rats aged 12-14 months, divided into four groups: a) Sham-operated control (SHAM) rats (n = 12), rats were fed a control diet (59% of food intake from carbohydrates, 7% from fat, 21% from protein, 13% from minerals and ash) for 12 weeks, b) High fat diet-fed control (HFD) group (n = 9), rats were fed a high fat diet (49% of food intake from carbohydrates, 17% from fat, 21% from protein, 13% from minerals and ash)for 12 weeks, c) Ovariectomized (OVX) rats (n = 14), rats were fed a control diet as SHAM rats, d) High fat diet- fed ovariectomized (OVX- HFD) rats (n = 13), rats were fed a high fat diet as HFD group. At the end of the experiment, blood samples were collected for calcium, phosphorus, and alkaline phosphatase (ALP) assays. Unilateral left perirenal fats were surgically removed and weighed. Specimens from right perirenal fats and tibia were isolated and processed for histological examination. Histomorphometric analysis of the tibia and visceral adipose tissue was also performed. RESULTS: OVX, HFD, and OVX-HFD rats showed a significant increase in relative visceral fat weight, and plasma ALP, and a significant decrease in plasma calcium, and phosphorus levels compared to SHAM rats. Light microscopic examination of the tibia of the OVX rats revealed a significant decrease in the cortical bone thickness (CBT) and the trabecular bone thickness (TBT), and a significant increase in bone marrow adipose tissue compared to SHAM rats. In addition, there was a significant increase in the osteoclast number, and a significant decrease in the osteoblast number. The changes in bone marrow adipose tissue as well as osteoclast number were further accentuated in OVX-HFD groups. CONCLUSIONS: Visceral obesity played a crucial role in the development of osteoporosis in ovariectomized rats through effects that might involve both osteoblasts and osteoclasts.

Impaired metabolic and hepatic functions following subcutaneous lipectomy in adult obese rats.

NEW FINDINGS: What is the central question of this study? What is the impact and drawbacks of subcutaneous lipectomy on body metabolism? What is the main finding and its importance? Subcutaneous lipectomy resulted in deterioration of hepatic functions, atherosclerotic lipid profile and disturbed redox state. While the results support lipectomy as an effective treatment for obesity, lipectomy induces unfavourable changes in health. ABSTRACT: The number of obese older adults is on the rise, but data about proper treatment of obesity in the elderly is controversial. The present study was designed to investigate the effectiveness and consequences of partial subcutaneous lipectomy, as a rapid medical intervention against increased accumulation of body fat, in adult obese rats. The study was conducted on adult (9-12 months) female rats, in which obesity was induced by bilateral surgical ovariectomy. They were randomized into two main groups: short term (5 weeks) and long term (10 weeks). Both groups were subdivided into control, ovariectomized (OVX) and ovariectomized lipectomized groups. Body weight (BW) was measured and body mass index (BMI) calculated. Fasting blood glucose, lipid profile and plasma levels of total proteins, albumin, liver enzymes, malondialdehyde (MDA), leptin and adiponectin were determined. The content of both blood and hepatic tissue of reduced glutathione was estimated. In addition, histological study of the liver, aorta and peri-renal fat was performed. Compared to controls, OVX rats showed significant increase in BW, BMI and plasma levels of liver enzymes, MDA and leptin. Histological study revealed vacuolated ballooned hepatocytes and enlarged irregular visceral adipocytes with atherosclerotic changes in the wall of aorta. Following subcutaneous lipectomy, rats exhibited significant fasting hyperglycaemia, dyslipidaemia, lowered plasma albumin and disturbed redox state with aggravation of the histological changes. The findings indicate that although subcutaneous lipectomy appears to be effective in combating obesity in older females, it has unfavourable effects on both metabolic and hepatic functions.