A New Ibuprofen Derivative Inhibits Platelet Aggregation and ROS Mediated Platelet Apoptosis

Abstract

Thrombocytopenia is a serious issue connected with the pathogenesis of several human diseases including chronic inflammation, arthritis, Alzheimer's disease, cardiovascular diseases (CVDs) and other oxidative stress-associated pathologies. The indiscriminate use of antibiotics and other biological drugs are reported to result in thrombocytopenia, which is often neglected during the treatment regime. In addition, augmented oxidative stress induced by drugs and pathological conditions has also been shown to induce thrombocytopenia, which seems to be the most obvious consequence of elevated rate of platelet apoptosis. Thus, blocking oxidative stress-induced platelet apoptosis would be of prime importance in order to negotiate thrombocytopenia and associated human pathologies. The current study presents the synthesis and platelet protective nature of novel ibuprofen derivatives. The potent anti-oxidant ibuprofen derivative 4f was selected for the study and the platelet protective efficacy and platelet aggregation inhibitory property has been demonstrated. The compound 4f dose dependently mitigates the oxidative stress-induced platelet apoptosis in both platelet rich plasma and washed platelets. The platelet protective nature of compound 4f was determined by assessing various apoptotic markers such as ROS generation, cytosolic Ca2+ levels, PS externalization, cytochrome C translocation, Caspase activation, mitochondrial membrane depolarization, cytotoxicity, LDH leakage and tyrosine phosphorylation of cytosolic proteins. Furthermore, compound 4f dose dependently ameliorated agonist induced platelet aggregation. Therefore, compound 4f can be estimated as a potential candidate in the treatment regime of pathological disorders associated with platelet activation and apoptosis. In addition, compound 4f can be used as an auxiliary therapeutic agent in pathologies associated with thrombocytopenia.

Treatment of Platelet Concentrates with the Mirasol Pathogen Inactivation System Modulates Platelet Oxidative Stress and NF-κB Activation

“…Oxidative stress occurs where excess ROS overwhelm endogenous antioxidant systems, resulting in damage to many cellular components, including proteins, lipids and nucleic acids, and subsequent apoptosis [21,22]. Hydrogen peroxide is capable of causing oxidative damage to platelet proteins [41], and a recent study demonstrates that riboflavin/UV treatment of platelets induces oxidative modification of selected peptides, such as fibronectin [42], and Mirasol treatment of plasma increases protein carbonylation [15].…”

“…As platelets generate ROS during activation [16,17] and ROS are capable of selectively modulating platelet activation [18,19], it is imperative to understand the role of Mirasol treatment in this context to ensure a complete understanding of the toxicological profile of this component [20]. Persistent high levels of ROS may overwhelm endogenous antioxidant systems, resulting in damage to proteins, lipids, and nucleic acids leading to apoptosis [21,22]. …”

Nano-MoO3-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching

“…18,19,29,30 In addition, deletion or over-expression of FtsK can result in the inhibition of cell division. 20 The docking scores (DS) of the docked compounds with the FtsK motor domain are summarized in Table 7.…”

“…Expansion of this chemotype enabled us to define the essential pharmacophore for Type III secretion inhibition by this structural class. 11,12 In a continuation of our work to synthesize and explore the pharmacological properties of various classes of heterocycles, [13][14][15][16][17][18][19][20] we report here the application of MoO 3 nanoparticles in the synthesis of novel thizolidin-4-ones, followed by their use as anti-bacterial agents against S. typhi and K. pneumoniae. Furthermore, we used chemogenomics approaches to predict protein targets in silico and rationalized the mode of action of the bioactive thiazolidin-4-one.…”

Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation

“…The development of thrombocytopenia in numerous human pathologies raises a need for the development of new molecules, which have the potential to alleviate stress-induced early platelet death. However, till date, very few molecules with platelet protective efficacy are reported, which includes natural compounds like crocin, cinnamtannin B1, and a synthetic derivatives of ibuprofen and N-acetyl cysteine with platelet protective efficacy [20]. Hence, search for novel synthetic platelet protective molecules with potential to combat against ROS-induced pathological conditions is essential in vascular pharmacology.…”