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1.
Diabetes Metab J ; 48(1): 1-18, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38173375

ABSTRACT

Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPRmt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPRmt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.


Subject(s)
Metabolic Diseases , Quality of Life , Humans , Mitochondria/metabolism , Metabolic Diseases/therapy , Metabolic Diseases/metabolism , Signal Transduction
2.
Cells ; 10(6)2021 05 24.
Article in English | MEDLINE | ID: mdl-34073755

ABSTRACT

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13-STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.


Subject(s)
Adipose Tissue/metabolism , Fibroblast Growth Factors/metabolism , Interleukin-33/metabolism , Animals , Gene Expression/physiology , Interleukin-4/metabolism , Liver/metabolism , Liver/pathology , Mice , PPAR alpha/metabolism , STAT6 Transcription Factor/metabolism
3.
Am J Transl Res ; 12(4): 1309-1318, 2020.
Article in English | MEDLINE | ID: mdl-32355543

ABSTRACT

Cell division cycle 20 homologue (Cdc20) is characterized as an oncoprotein that is involved in carcinogenesis. Accumulated evidence reveals that Cdc20 plays an oncogenic role by governing cell growth, apoptosis, motility, and metastasis. The role of Cdc20 in drug resistance is elusive. In the present study, we exploited whether Cdc20 is involved in the cisplatin (DDP) resistance-induced epithelial-mesenchymal transition (EMT) of osteosarcoma cells. We found that DDP resistant U2OS and MG63 cells underwent EMT. Moreover, DDP-resistant cells exhibit the mesenchymal features such as enhanced attachment and detachment and increased invasion activity and migration. Mechanistically, Cdc20 was highly expressed in DDP-resistant osteosarcoma cells compared to parental cells. Consistently, downregulation of CdcC20 in DDP-resistant cells reversed the EMT phenotypes and changed the expression of EMT biomarkers. Our studies provide evidence for targeting Cdc20 as a promising approach to enhancing drug sensitivity for the treatment of osteosarcoma.

4.
Oncol Rep ; 40(2): 841-848, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29901174

ABSTRACT

Osteosarcoma (OS) is the most common primary malignant bone tumor worldwide, primarily affecting children and adolescents. The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that is activated by its co­activator Cdc20 during the metaphase­anaphase transition. Apcin is a novel cell­permeable molecule that blocks the interaction between APC/C and Cdc20. Cdc20 overexpression has been reported in various malignancies and plays an oncogenic role in tumorigenesis and tumor progression. In the present study, the antitumor properties of apcin, an inhibitor of Cdc20, was investigated in OS cell lines. In addition, the possible molecular target by which apcin mediates cell death was explored. Apcin was demonstrated to inhibit OS cell growth and induce significant apoptosis. The invasion and mobile abilities of OS cells were also markedly suppressed by apcin treatment. Furthermore, Bim and p21 were upregulated in OS cells following apcin treatment. The results of the present study indicated that apcin may have therapeutic potential as a treatment for OS and that Cdc20 may be a promising molecular target for chemotherapy.


Subject(s)
Carbamates/pharmacology , Cdc20 Proteins/antagonists & inhibitors , Cell Proliferation/drug effects , Diamines/pharmacology , Osteosarcoma/drug therapy , Apoptosis/drug effects , Bcl-2-Like Protein 11/metabolism , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Disease Progression , Humans , Up-Regulation/drug effects
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