Interleukin-6 (IL-6) signaling network has been implicated in oncogenic transformations making it attractive target for the discovery of novel cancer therapeutics. In this study, potent antiproliferative and apoptotic effect of diacerein were observed against breast cancer. In vitro apoptosis was induced by this drug in breast cancer cells as verified by increased sub-G1 population, LIVE/DEAD assay, cell cytotoxicity and presence of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, as well as downregulation of antiapoptotic proteins Bcl-2 and Bcl-xL and upregulation of apoptotic protein Bax. In addition, apoptosis induction was found to be caspase dependent. Further molecular investigations indicated that diacerein instigated apoptosis was associated with inhibition of IL-6/IL-6R autocrine signaling axis. Suppression of STAT3, MAPK and Akt pathways were also observed as a consequence of diacerein-mediated upstream inhibition of IL-6/IL-6R. Fluorescence study and western blot analysis revealed cytosolic accumulation of STAT3 in diacerein-treated cells. The docking study showed diacerein/IL-6R interaction that was further validated by competitive binding assay and isothermal titration calorimetry. Most interestingly, it was found that diacerein considerably suppressed tumor growth in MDA-MB-231 xenograft model. The in vivo antitumor effect was correlated with decreased proliferation (Ki-67), increased apoptosis (TUNEL) and inhibition of IL-6/IL-6R-mediated STAT3, MAPK and Akt pathway in tumor remnants. Taken together, diacerein offered a novel blueprint for cancer therapy by hampering IL-6/IL-6R/STAT3/MAPK/Akt network.
One of the greatest challenges for widespread utilization of solar energy is the low conversion efficiency, motivating the needs of developing more innovative approaches to improve the design of solar energy conversion equipment. Solar cell is the fundamental component of a photovoltaic (PV) system. Solar cell's precise modelling and estimation of its parameters are of paramount importance for the simulation, design, and control of PV system to achieve optimal performances. It is nontrivial to estimate the unknown parameters of solar cell due to the nonlinearity and multimodality of search space. Conventional optimization methods tend to suffer from numerous drawbacks such as a tendency to be trapped in some local optima when solving this challenging problem. This paper aims to investigate the performance of eight state-of-the-art metaheuristic algorithms (MAs) to solve the solar cell parameter estimation problem on four case studies constituting of four different types of PV systems: R.T.C. France solar cell, LSM20 PV module, Solarex MSX-60 PV module, and SS2018P PV module. These four cell/modules are built using different technologies. The simulation results clearly indicate that the Coot-Bird Optimization technique obtains the minimum RMSE values of 1.0264E-05 and 1.8694E-03 for the R.T.C. France solar cell and the LSM20 PV module, respectively, while the wild horse optimizer outperforms in the case of the Solarex MSX-60 and SS2018 PV modules and gives the lowest value of RMSE as 2.6961E-03 and 4.7571E-05, respectively. Furthermore, the performances of all eight selected MAs are assessed by employing two non-parametric tests known as Friedman ranking and Wilcoxon rank-sum test. A full description is also provided, enabling the readers to understand the capability of each selected MA in improving the solar cell modelling that can enhance its energy conversion efficiency. Referring to the results obtained, some thoughts and suggestions for further improvements are provided in the conclusion section.
The coagulation and immune system, both essential physiological systems in the human body, are intricately interconnected and play a critical role in determining the overall health of patients. These systems collaborate via various shared regulatory pathways, such as the Tissue Factor (TF) Pathway. Immunological cells that express TF and generate pro-inflammatory cytokines have the ability to affect coagulation. Conversely, coagulation factors and processes have a reciprocal effect on immunological responses by stimulating immune cells and regulating their functions. These interconnected pathways play a role in both preserving well-being and contributing to a range of pathological disorders. The close relationship between blood clotting and inflammation in the development of vascular disease has become a central focus of clinical study. This research specifically examines the crucial elements of this interaction within the contexts of cardiovascular disease and acute coronary syndrome. Tissue factor, the primary trigger of the extrinsic coagulation pathway, has a crucial function by inducing a proinflammatory reaction through the activation of coagulation factors. This, in turn, initiates coagulation and subsequent cellular signalling pathways. Protease-activated receptors establish the molecular connection between coagulation and inflammation by interacting with activated clotting factors II, X, and VII. Thrombosis, a condition characterised by the formation of blood clots, is the most dreaded consequence of cardiovascular disorders and a leading cause of death globally. Consequently, it poses a significant challenge to healthcare systems. Antithrombotic treatments efficiently target platelets and the coagulation cascade, but they come with the inherent danger of causing bleeding. Furthermore, antithrombotics are unable to fully eliminate thrombotic events, highlighting a treatment deficiency caused by a third mechanism that has not yet been sufficiently addressed, namely inflammation. Understanding these connections may aid in the development of novel approaches to mitigate the harmful mutual exacerbation of inflammation and coagulation. Gaining a comprehensive understanding of the intricate interaction among these systems is crucial for the management of diseases and the creation of efficacious remedies. Through the examination of these prevalent regulatory systems, we can discover novel therapeutic approaches that specifically target these complex illnesses. This paper provides a thorough examination of the reciprocal relationship between the coagulation and immune systems, emphasising its importance in maintaining health and understanding disease processes. This review examines the interplay between inflammation and thrombosis and its role in the development of thrombotic disorders.