Novel smac mimetic ASTX660 (Tolinapant) and TNF-α synergistically induce necroptosis in bladder cancer cells in vitro upon apoptosis inhibition.

Apoptosis inhibition often leads to resistance to chemotherapeutics in bladder cancer (BC), resulting in poor prognosis of patients. Accumulating evidence suggests that induction of necroptosis, another type of programmed cell death, can be applied as an alternative strategy to kill apoptosis-insensitive BC cells. In this study, we showed that a novel Smac mimetic, ASTX660, also known as Tolinapant, can induce necroptosis in BC cells when apoptosis is inhibited. This is achieved by turning tumour necrosis factor (TNF)-α into a cytotoxic signal; ASTX660 then acts synergistically with TNF-α to induce necroptosis in BC cells. Mechanistic investigation showed that ASTX660 promoted the formation of the necrosome complex. Genetic or pharmacological inhibition of RIP1, RIP3, or MLKL, which are components of necrosome complex, provided protection against cell death induced by ASTX660 alone or ASTX660/TNF-α upon caspase inhibition. In addition, TNF-α/TNFR1 signalling and IRF1 are essential for the necroptosis induced by ASTX660 after the caspases are blocked. Our study highlights that ASTX660 can overcome the limitation of apoptosis induction via triggering necroptosis in BC cells. Therefore, our findings may provide some important clues for the design of a novel treatment strategy for BC.

Ipatasertib (GDC-0068) and erdafitinib co-treatment for inducing mitochondrial apoptosis through Bim upregulation in bladder cancer cells.

Bladder cancer (BC) is a common malignancy of the urological system that still lacks effective treatment. It is frequently characterised by dysregulation of fibroblast growth factor receptor (FGFR) signalling. FGFR inhibitors have been proven as a promising treatment for BC in clinical settings. Besides the FGFR signalling, the therapeutic effects of FGFR inhibitors are often limited owing to various mechanisms, such as the activation of the Akt signalling pathway. Therefore, this study aimed to examine the synergistic effects of ipatasertib, a FGFR inhibitor, and erdafitinib, an Akt inhibitor, in BC cells. Ipatasertib and erdafitinib co-treatment synergistically inhibited cell proliferation and induced BC cell death. Mechanically, ipatasertib and erdafitinib induced the activation of Bax, an essential protein for cell death. Moreover, erdafitinib, which inhibited the Akt signalling pathway, is responsible for Bim upregulation, a condition critical to achieving the synergistic effects. Therefore, our data suggest that ipatasertib and erdafitinib co-treatment is a promising strategy for BC.

Phytol increases adipocyte number and glucose tolerance through activation of PI3K/Akt signaling pathway in mice fed high-fat and high-fructose diet.

It has been shown that adipose tissue hyperplasia (increased adipocyte number or adipogenesis) has beneficial effects on metabolic health. The aim of the present study was to determine whether phytol could modulate hyperplasia/adipogenesis and glucose homeostasis, and to explore the underlying mechanisms in mice fed high-fat and high fructose diet (HFFD). Our results demonstrated that phytol administration decreased body weight gain and inguinal subcutaneous white adipose tissue (iWAT) weight. However, phytol significantly increased the adipocyte number in iWAT, with the smaller average adipocyte diameter. Meanwhile, OGTT result showed that phytol improved glucose tolerance. In accord, phytol administration markedly increased expression of marker genes associated with adipogenesis (PPARγ and C/EBPα) and glucose uptake (AS160 and GLUT4) and activated PI3K/Akt signaling pathway in mice iWAT. In agreement with the in vivo findings, the in vitro results indicated that 100 µM phytol significantly enhanced 3T3-L1 adipogenesis and glucose uptake, and activated PI3K/Akt signaling pathway. However, phytol-induced enhancement of 3T3-L1 adipognesis and glucose uptake, activation of PI3K/Akt signaling pathway, elevation of marker genes involved in adipogensis and glucose uptake, as well as translocation of GLUT4 from cytoplasm to membrane were abolished by Wortmannin, a specific PI3K/Akt inhibitor. Taken together, phytol increased adipocyte number in iWAT and improved glucose tolerance in mice fed HFFD, which was coincident with the enhanced adipogenesis and glucose uptake in 3T3-L1, and was associated with activation of PI3K/Akt signaling pathway. These data suggested the application of phytol as a potential nutritional agent to combat obesity and type 2 diabetes.

Misdiagnosis of cystic tuberculosis of the olecranon.

Osteoarticular tuberculosis accounts for only 1-2% of all cases of tuberculosis, and tuberculosis of the olecranon is extremely rare. In the present study, we describe a case of a 54-year-old woman with cystic tuberculosis of the olecranon, which was initially misdiagnosed as a malignant tumor. The patient subsequently underwent regular antituberculosis treatment and autogenous bone graft, which resulted in relief of all symptoms.

Phytol stimulates the browning of white adipocytes through the activation of AMP-activated protein kinase (AMPK) α in mice fed high-fat diet.

Stimulating the browning of white adipocytes contributes to the restriction of obesity and related metabolic disorders. This study aimed to investigate the browning effects of phytol on mice inguinal subcutaneous white adipose tissue (iWAT) and explore the underlying mechanisms. Our results demonstrated that phytol administration decreased body weight gain and iWAT index, and stimulated the browning of mice iWAT, with the increased expression of brown adipocyte marker genes (UCP1, PRDM16, PGC1α, PDH, and Cyto C). In addition, phytol treatment activated the AMPKα signaling pathway in mice iWAT. In good agreement with the in vivo findings, the in vitro results showed that 100 µM phytol stimulated brown adipogenic differentiation and formation of brown-like adipocytes in the differentiated 3T3-L1 by increasing the mitochondria content and oxygen consumption, and promoting mRNA and/or protein expression of brown adipocyte markers (UCP1, PRDM16, PGC1α, PDH, Cyto C, Cidea and Elovl3) and beige adipocyte markers (CD137 and TMEM26). Meanwhile, phytol activated the AMPKα signaling pathway in the differentiated 3T3-L1. However, the inhibition of AMPKα with Compound C totally abolished phytol-stimulated brown adipogenic differentiation and formation of brown-like adipocytes. In conclusion, these results showed that phytol stimulated the browning of mice iWAT, which was coincident with the increased formation of brown-like adipocytes in the differentiated 3T3-L1, and appeared to be primarily mediated by the AMPKα signaling pathway. These data provided new insight into the role of phytol in regulating the browning of WAT and suggested the potential application of phytol as a nutritional intervention for the restriction of obesity and related metabolic disorders.

Hypolipidemic Activity and Antiatherosclerotic Effect of Polysaccharide of Polygonatum sibiricum in Rabbit Model and Related Cellular Mechanisms.

Objective. To evaluate the hypolipidemic activity and antiatherosclerotic effect of polysaccharide of Polygonatum sibiricum (PPGS), which is a kind of Chinese herbal medicine using the rhizome part of the whole herb. Materials and Methods. Thirty rabbits were divided into normal control group, model control group, and PPGS subgroups of 0.8, 1.6, and 3.2 mL/kg/day under random selection. In atherosclerosis model, the effects of PPGS on diverse blood lipids, foam cells number, and aortic morphology were evaluated. In the primary culture of endothelial cells (ECs), the activities of PPGS on both ECs proliferation and ECs injury were studied as well. Results. In atherosclerosis model, the hypolipidemic activities of PPGS were mainly focused on TC, LDL-C, and Lp(a). All changes on these factors were statistically significant compared with model group (P < 0.01), except TG and HDL-C. The intimal foam cell number of PPGS subgroups (0.8, 1.6, and 3.2 mL/kg/day) was significantly reduced than model control (P < 0.01). In the primary culture of endothelial cells (ECs), PPGS showed no effect on cell proliferation but preferred to protect EC from injury and apoptosis induced by H2O2 and lipopolysaccharide (LPS). Discussion and Conclusion. The antiatherosclerotic effect of PPGS may be supported by its hypolipidemic activities, improving aortic morphology, and reducing foam cells number and ECs injury.