ATP-induced cell death has emerged as a captivating realm of inquiry with profound ramifications in the context of osteoporosis. This study unveils a paradigm-shifting hypothesis that illuminates the prospective involvement of ATP-induced cellular demise in the etiology of osteoporosis. Initially, we explicate the morphological attributes of ATP-induced cell death and delve into the intricacies of the molecular machinery and regulatory networks governing ATP homeostasis and ATP-induced cell death. Subsequently, our focus pivots towards the multifaceted interplay between ATP-induced cellular demise and pivotal cellular protagonists, such as bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts, accentuating their potential contributions to secondary osteoporosis phenotypes, encompassing diabetic osteoporosis, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis. Furthermore, we probe the captivating interplay between ATP-induced cellular demise and alternative modalities of cellular demise, encompassing apoptosis, autophagy, and necroptosis. Through an all-encompassing inquiry into the intricate nexus connecting ATP-induced cellular demise and osteoporosis, our primary goal is to deepen our comprehension of the underlying mechanisms propelling this malady and establish a theoretical bedrock to underpin the development of pioneering therapeutic strategies.
One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds.
Adenosine triphosphate (ATP) induced cell death (AICD) is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions. This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology. This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer. This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis, deciphering the intricate mechanisms governing AICD, elucidating its intricate involvement in cancer signaling pathways, and scrutinizing validated key genes. Moreover, the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.