Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway.
 ...
PMID:Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration. 2873 43

Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword 'metformin' plus the following terms: 'thyroid cancer', 'thyroid nodules', 'parathyroid', 'hyperparathyroidism', 'adrenal adenoma', 'Cushing syndrome', 'hyperaldosteronism', 'adrenocortical cancer', 'neuroendocrine tumor (NET)', 'pancreatic NET (pNET)', 'carcinoid', 'pituitary adenoma', 'pituitary neuroendocrine tumor (PitNET)', 'prolactinoma', 'pheochromocytoma/paraganglioma'. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.
 ...
PMID:The role of an anti-diabetic drug metformin in the treatment of endocrine tumors. 3130 11

Primary aldosteronism (PA) is characterized by aldosterone hypersecretion and adrenal hyperplasia and ranks as one of the most common causes of secondary hypertension. However, the molecular mechanism involved in adrenal hyperplasia and tumorigenesis is largely unknown. Dysregulation of Purkinji cell protein 4 (PCP4) is involved in the development and progression of neoplasia and aldosterone secretion, but little is known about the effect of PCP4 on human adrenocortical tumorigenesis. We investigated the expression pattern of PCP4 in different adrenal tissues and studied whether PCP4 is involved in cell growth in human adrenal cell lines. The mRNA levels of PCP4 were measured by real-time PCR in tissues from aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism (IHA) tissues, and normal adrenal (NA) tissues. In vitro siRNA knockdown of PCP4 in NCI-H295R and SW13 cell lines was used to determine the effect of PCP4 on cellular growth. Our results show that the mRNA level of PCP4 is upregulated in APAs and IHA compared with that in NA. The PCP4 mRNA expression level was positively correlated with tumor size in APAs. Knockdown of PCP4 decreased cell proliferation. Flow cytometry analysis showed that PCP4 knockdown fosters apoptosis. Finally, PCP4 knockdown inhibited phosphorylation of AKT308 and AMPKThr172. Our data suggest that PCP4 may represent a key player in the development and pathophysiology of PA via targeting the AKT and AMPK signaling pathways and thus may be a promising therapeutic target for PA.
 ...
PMID:Upregulation of PCP4 in human aldosterone-producing adenomas fosters human adrenocortical tumor cell growth via AKT and AMPK pathway. 3193 14