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    • br Concluding remarks Following the disappointing outcomes o

    2023-10-26


    Concluding remarks Following the disappointing outcomes of Aβ immunotherapy trials for AD [62], the current prevailing concept is that disease-modifying therapy must be initiated from the presymptomatic stage of the disease because of the presumed incurability of chronic diseases once they become symptomatic [63]. Regardless, treatment should ideally be as aggressively as possible even in the advanced stage. In this context, we propose a novel concept of APN-related therapy, in which antagonist-driven inhibition of the APN receptor signaling pathway might further ameliorate disease pathology and symptoms (Fig. 3). Hopefully, therapeutic outcomes could be monitored and directed by measuring serum APN as a biomarker. This is important because no good biomarkers are presently available for assessment of therapeutic effects in AD. Furthermore, a similar dual strategy of stimulation and inhibition of the APN receptor might also be of benefit for the treatment of cancer and other chronic diseases that involve the obesity paradox. However, the benefit–risk ‘trade-offs’ with other diseases, the absence of good preclinical disease models of the APN paradox, and the lack of a fundamental understanding of APN activity under pathological conditions remain challenges in APN-based dual therapy. Further investigations are required to obtain a better understanding of the pathological roles of APN signaling in chronic disorders, such as AD, CHF and CKD, toward fulfilling the promise of APN-related drug discovery.
    Acknowledgment
    Introduction Adiponectin, also called GBP-28, apM1, AdipoQ, and Acrp30, has been discovered to be an adipocyte secreted hormone. It is a protein of 244 Tanespimycin and the product of the apM1 gene, which is specifically expressed in human adipocytes [1]. Adiponectin, a member of adipokines, has been found to be an important negative regulator of hematopoiesis and linked mainly to the risk of Chronic myeloid leukemia (CML) [2]. It is well established that Adiponectin has modulated cell proliferation and apoptosis via two distinct receptors: Adiponectin Receptor-1 (AdipoR1) and Adiponectin Receptor-2 (AdipoR2) [3], [4]. Moreover, a recent report has revealed that AdipoR1 expression was significantly increased in the mononuclear cells in CML patients, and this increase was similar in newly diagnosed and in imatinib treated CML patients [5], on the other hand, imatinib could increase Adiponectin secretion through the suppression of PI3 kinase signaling [6]. Furthermore, Adiponectin levels are elevated in CML patient plasma after imatinib therapy [7]. Taken together, it is tempting to hypothesize that Adiponectin and its functional receptor AdipoR1 might be involved in regulation of imatinib responding in CML treatment. CML is a hematopoietic stem cell disorder with an elevated but immature white blood cell count [8]. CML is generally diagnosed by the presence of an abnormal Philadelphia (Ph) chromosome, which results from a translocation between the long arms of chromosomes 9 and 22. This exchange brings the Bcr gene and the proto-oncogene Abl together [9]. The hybrid gene, Bcr-Abl, encodes for a fusion protein with tyrosine kinase activity leading to uncontrolled growth. One of the major achievements in the treatment of CML has been the development of the first tyrosine-kinase inhibitor imatinib mesylate (STI571, Gleevec), a phenylaminopyrimidine derivative. Imatinib directly occupies the ATP-binding pocket of the Abl-kinase domain, and prevents conformation change of the protein into the active form [10], with the subsequent regulation on transcription of several genes involved in the control of cell cycle, cell adhesion, and cytoskeleton organization, leading to apoptosis of target cells [11]. Despite high rates of hematological and cytogenetic responses to therapy, the emergence of resistance to imatinib has been recognized as a major problem in CML treatment [12], [13]. So far, mechanisms identified in development of imatinib-resistance include overexpression of Bcr-Abl associated with amplification or mutation of Bcr-Abl, and overexpression of the multidrug-resistant P-glycoprotein (MDR-1) [14], [15], [16]. Although considerable progress has been made in the elucidation of the mechanisms of resistance, we are still far from understanding the cause of this resistance and the proper solution to reverse imatinib resistance in human CML cells [13].