The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

McClements, Lana; Annett, Stephanie; Yakkundi, Anita; Robson, Tracy

doi:10.2174/1874467208666150519115729

Cited by 17 publications

(23 citation statements)

References 241 publications

(222 reference statements)

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“…CypA is involved in multiple processes such as endothelial dysfunction, modulation of smooth muscle cells, Cyclophilins in Ischemic Heart Disease Cardiol Res. 2020;11(5):319-327 fibroblast and cardiac hypertrophy [2,5]. Even more, CypA levels can be used to predict all-cause death, rehospitalization, and coronary revascularization in patients with CAD [9].…”

Section: Discussionmentioning

confidence: 99%

“…CypA is released to the extracellular media in response to inflammation. CypA is involved in multiple processes such as endothelial dysfunction, modulation of smooth muscle cells, fibroblast and cardiac hypertrophy [ 2 , 5 ]. Even more, CypA levels can be used to predict all-cause death, rehospitalization, and coronary revascularization in patients with CAD [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cyps are some of the most conserved proteins present in eukaryotes and prokaryotes, and they have been implicated in diverse cellular processes and responses to multiple biotic and abiotic stresses [3]. Some of these proteins, such as CypA, CypB, CypD or FKBP51, have been previously associated with CAD [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, Cyps are related to redox homeostasis, and redox-mediated signal-Cyclophilins in Ischemic Heart Disease Cardiol Res. 2020;11 (5):319-327…”

Section: Introductionmentioning

confidence: 99%

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Cyclophilins in Ischemic Heart Disease: Differences Between Acute and Chronic Coronary Artery Disease Patients

et al. 2020

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Background: Cyclophilins (Cyps) are a family of peptidyl-prolyl cis/trans isomerases consistently involved in cardiovascular diseases through the inflammation pathway. This study aims to investigate the serum levels of Cyps (CypA, CypB, CypC and CypD) in patients with coronary artery disease (CAD) and the correlation with clinical characteristics and inflammation parameters. Methods: We developed an observational prospective study with a total of 125 subjects: 40 patients with acute CAD, 40 patients with chronic CAD and 45 control volunteers, in whom serum levels of Cyps (CypA, CypB, CypC and CypD), interleukins and metalloproteinases were measured. Results: CypA levels increased significantly in CAD patients compared with control subjects, but no differences were noted between acute CAD (7.80 ± 1.30 ng/mL) and chronic CAD (5.52 ± 0.76 ng/mL) patients (P = 0.13). No differences in CypB and CypD levels were showed between CAD patients and controls and between acute CAD and chronic CAD patients. In relation with CypC, the levels in CAD patients were significantly higher compared to controls (32.42 ± 3.71 pg/mL vs. 9.38 ± 1.51 pg/mL, P < 0.001), but no differences between acute and chronic CAD groups were obtained (P = 0.62). We analyzed the CypC > 17.5 pg/mL cutoff point, and it was significantly associated with older age, hypertension, dyslipidemia and more extensive CAD in acute and chronic CAD groups. Conclusions: CypA and CypC levels are increased in CAD patients. High CypC serum levels could be a novel biomarker in CAD patients correlating with a more severe disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In addition, Cyps are related to redox homeostasis, and redox-mediated signal-Cyclophilins in Ischemic Heart Disease Cardiol Res. 2020;11 (5):319-327…”

Section: Introductionmentioning

confidence: 99%

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Cyclophilins in Ischemic Heart Disease: Differences Between Acute and Chronic Coronary Artery Disease Patients

et al. 2020

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“…FK506-binding protein like (FKBPL) is a novel anti-tumour protein that belongs to the family of immunophilins, but is a divergent member lacking peptidyl prolyl isomerase activity [19]. Immunophilins orchestrate protein-protein interactions therefore regulating many cellular processes including cell signalling, differentiation, cell cycle progression, metabolic activity and apoptosis [20]. FKBPL has diverse anti-tumour roles both as an intracellular and extracellular protein.…”

Section: Introductionmentioning

confidence: 99%

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

et al. 2019

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Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER-and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER-MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, preclinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER-breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

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Mitochondrial–nuclear communication by FKBP51 shuttling

Zgajnar

Lagadari

Gallo

et al. 2023

J of Cellular Biochemistry

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The HSP90‐binding immunophilin FKBP51 is a soluble protein that shows high homology and structural similarity with FKBP52. Both immunophilins are functionally divergent and often show antagonistic actions. They were first described in steroid receptor complexes, their exchange in the complex being the earliest known event in steroid receptor activation upon ligand binding. In addition to steroid‐related events, several pleiotropic actions of FKBP51 have emerged during the last years, ranging from cell differentiation and apoptosis to metabolic and psychiatric disorders. On the other hand, mitochondria play vital cellular roles in maintaining energy homeostasis, responding to stress conditions, and affecting cell cycle regulation, calcium signaling, redox homeostasis, and so forth. This is achieved by proteins that are encoded in both the nuclear genome and mitochondrial genes. This implies active nuclear‐mitochondrial communication to maintain cell homeostasis. Such communication involves factors that regulate nuclear and mitochondrial gene expression affecting the synthesis and recruitment of mitochondrial and nonmitochondrial proteins, and/or changes in the functional state of the mitochondria itself, which enable mitochondria to recover from stress. FKBP51 has emerged as a serious candidate to participate in these regulatory roles since it has been unexpectedly found in mitochondria showing antiapoptotic effects. Such localization involves the tetratricopeptide repeats domains of the immunophilin and not its intrinsic enzymatic activity of peptidylprolyl‐isomerase. Importantly, FKBP51 abandons the mitochondria and accumulates in the nucleus upon cell differentiation or during the onset of stress. Nuclear FKBP51 enhances the enzymatic activity of telomerase. The mitochondrial‐nuclear trafficking is reversible, and certain situations such as viral infections promote the opposite trafficking, that is, FKBP51 abandons the nucleus and accumulates in mitochondria. In this article, we review the latest findings related to the mitochondrial‐nuclear communication mediated by FKBP51 and speculate about the possible implications of this phenomenon.

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The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

Cited by 17 publications

References 241 publications

Cyclophilins in Ischemic Heart Disease: Differences Between Acute and Chronic Coronary Artery Disease Patients

Cyclophilins in Ischemic Heart Disease: Differences Between Acute and Chronic Coronary Artery Disease Patients

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

Mitochondrial–nuclear communication by FKBP51 shuttling

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