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A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis (2024)
Journal Article
Watkins, R., Gamo, A., Choi, S. H., Kumar, M., Buckarma, E. L., McCabe, C., Tomlinson, J., Pereya, D., Lupse, B., Geravandi, S., Werneburg, N. W., Wang, C., Starlinger, P., Zhu, S., Li, S., Yu, S., Surakattula, M., Baguley, T., Ardestani, A., Maedler, K., …Smoot, R. (2024). A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis. PNAS Nexus, 3(3), Article pgae096. https://doi.org/10.1093/pnasnexus/pgae096

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis c... Read More about A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis.

The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance (2023)
Journal Article
Mahmoudi-Aznaveh, A., Tavoosidana, G., Najmabadi, H., Azizi, Z., & Ardestani, A. (2023). The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance. Frontiers in endocrinology, 14, Article 1303930. https://doi.org/10.3389/fendo.2023.1303930

Introduction: An insufficient functional beta cell mass is a core pathological hallmark of type 2 diabetes (T2D). Despite the availability of several effective pharmaceuticals for diabetes management, there is an urgent need for novel medications to... Read More about The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance.

Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer (2022)
Journal Article
Angelis, V., Johnston, S. R., Ardestani, A., & Maedler, K. (2022). Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer. Frontiers in endocrinology, 13, Article 830097. https://doi.org/10.3389/fendo.2022.830097

A critical decline of functional insulin-producing pancreatic β-cells is the central pathologic element of both type 1 and type 2 diabetes. Mammalian Sterile 20-like kinase 1 (MST1) is a key mediator of β-cell failure and the identification of nerati... Read More about Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer.

MST1 deletion protects β-cells in a mouse model of diabetes (2022)
Journal Article
Ardestani, A., & Maedler, K. (2022). MST1 deletion protects β-cells in a mouse model of diabetes. Nutrition and Diabetes, 12(1), Article 7. https://doi.org/10.1038/s41387-022-00186-3

The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological... Read More about MST1 deletion protects β-cells in a mouse model of diabetes.

The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis (2021)
Journal Article
Yuan, T., Annamalai, K., Naik, S., Lupse, B., Geravandi, S., Pal, A., …Ardestani, A. (2021). The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis. Nature communications, 12(1), Article 4928. https://doi.org/10.1038/s41467-021-25145-x

Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signa... Read More about The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis.

Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes (2021)
Journal Article
Lupse, B., Annamalai, K., Ibrahim, H., Kaur, S., Geravandi, S., Sarma, B., …Ardestani, A. (2021). Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell reports, 36(5), Article 109490. https://doi.org/10.1016/j.celrep.2021.109490

Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphat... Read More about Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes.

LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes (2021)
Journal Article
Sanchez, P. K. M., Khazaei, M., Gatineau, E., Geravandi, S., Lupse, B., Liu, H., …Ardestani, A. (2021). LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes. Biochemical and biophysical research communications, 568, 158-166. https://doi.org/10.1016/j.bbrc.2021.06.065

The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult β-cel... Read More about LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes.

Hippo STK kinases drive metabolic derangement (2021)
Journal Article
Maedler, K., & Ardestani, A. (2021). Hippo STK kinases drive metabolic derangement. Nature Metabolism, 3(3), 295-296. https://doi.org/10.1038/s42255-021-00370-2

Obesity is associated with mitochondrial dysfunction and chronic metabolic derailment. Cho et al. report that elevated adipose expression of the Hippo kinases STK3 and STK4 (STK3/4) in obesity and type 2 diabetes decreases the mass and oxidative capa... Read More about Hippo STK kinases drive metabolic derangement.

Neratinib protects pancreatic beta cells in diabetes (2019)
Journal Article
Ardestani, A., Li, S., Annamalai, K., Lupse, B., Geravandi, S., Dobrowolski, A., …Maedler, K. (2019). Neratinib protects pancreatic beta cells in diabetes. Nature communications, 10(1), Article 5015. https://doi.org/10.1038/s41467-019-12880-5

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The ide... Read More about Neratinib protects pancreatic beta cells in diabetes.

An SCFfbxo28 E3 ligase protects pancreatic β-cells from apoptosis (2018)
Journal Article
Gorrepati, K. D. D., He, W., Lupse, B., Yuan, T., Maedler, K., & Ardestani, A. (2018). An SCFfbxo28 E3 ligase protects pancreatic β-cells from apoptosis. International Journal of Molecular Sciences, 19(4), Article 975. https://doi.org/10.3390/ijms19040975

Loss of pancreatic β-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. β-cell apoptosis contributes to the reduced β-cell mass in diabetes. Therefore, the identification of im... Read More about An SCFfbxo28 E3 ligase protects pancreatic β-cells from apoptosis.

Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response (2018)
Journal Article
Gorrepati, K. D. D., Lupse, B., Annamalai, K., Yuan, T., Maedler, K., & Ardestani, A. (2018). Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response. iScience, 1, 72-86. https://doi.org/10.1016/j.isci.2018.02.003

Impaired pancreatic β-cell survival contributes to the reduced β-cell mass in diabetes, but underlying regulatory mechanisms and key players in this process remain incompletely understood. Here, we identified the deubiquitinase ubiquitin-specific pro... Read More about Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response.

mTORC in β cells: More Than Only Recognizing Comestibles (2017)
Journal Article
Maedler, K., & Ardestani, A. (2017). mTORC in β cells: More Than Only Recognizing Comestibles. Journal of Cell Biology, 216(7), 1883-1885. https://doi.org/10.1083/jcb.201704179

The pathways regulating pancreatic β cell survival in diabetes are poorly understood. Here, Chau et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701085) demonstrate that mTOR regulates the apoptotic machinery through binding to the ChREBP-... Read More about mTORC in β cells: More Than Only Recognizing Comestibles.

Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes (2016)
Journal Article
Yuan, T., Rafizadeh, S., Gorrepati, K. D. D., Lupse, B., Oberholzer, J., Maedler, K., & Ardestani, A. (2017). Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes. Diabetologia, 60(4), 668-678. https://doi.org/10.1007/s00125-016-4188-9

Aims/hypothesis: Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancr... Read More about Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes.

Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells (2016)
Journal Article
Yuan, T., Rafizadeh, S., Azizi, Z., Lupse, B., Devi Gorrepati, K. D., Awal, S., …Ardestani, A. (2016). Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells. JCI Insight, 1(18), Article e86326. https://doi.org/10.1172/jci.insight.86326

Loss of functional pancreatic β cells is a hallmark of both type 1 and 2 diabetes. Identifying the pathways that promote β cell proliferation and/or block β cell apoptosis is a potential strategy for diabetes therapy. The transcriptional coactivator... Read More about Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells.

Angiopoetin-2 signals do not mediate the hypervascularization of islets in type 2 diabetes (2016)
Journal Article
Shah, P., Lueschen, N., Ardestani, A., Oberholzer, J., Olerud, J., Carlsson, P. O., & Maedler, K. (2016). Angiopoetin-2 signals do not mediate the hypervascularization of islets in type 2 diabetes. PLoS ONE, 11(9), Article e0161834. https://doi.org/10.1371/journal.pone.0161834

Aims Changes in the islet vasculature have been implicated in the regulation of β-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the β-cell to compensate for the increased insulin demand in obesity eventually l... Read More about Angiopoetin-2 signals do not mediate the hypervascularization of islets in type 2 diabetes.

β-MSCs: Successful fusion of MSCs with β-cells results in a β-cell like phenotype (2016)
Journal Article
Azizi, Z., Lange, C., Paroni, F., Ardestani, A., Meyer, A., Wu, Y., …Maedler, K. (2016). β-MSCs: Successful fusion of MSCs with β-cells results in a β-cell like phenotype. Oncotarget, 7(31), 48963-48977. https://doi.org/10.18632/oncotarget.10214

Bone marrow mesenchymal stromal cells (MSC) have anti-inflammatory, antiapoptotic and immunosuppressive properties and are a potent source for cell therapy. Cell fusion has been proposed for rapid generation of functional new reprogrammed cells. In t... Read More about β-MSCs: Successful fusion of MSCs with β-cells results in a β-cell like phenotype.

MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes (2014)
Journal Article
Ardestani, A., Paroni, F., Azizi, Z., Kaur, S., Khobragade, V., Yuan, T., …Maedler, K. (2014). MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nature Medicine, 20(4), 385-397. https://doi.org/10.1038/nm.3482

Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and strategies to prevent beta cell apoptosis and dysfunction... Read More about MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes.

The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization (2013)
Journal Article
Shah, P., Ardestani, A., Dharmadhikari, G., Laue, S., Schumann, D. M., Kerr-Conte, J., …Maedler, K. (2013). The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization. Journal of Clinical Endocrinology and Metabolism, 98(7), E1163–E1172. https://doi.org/10.1210/jc.2013-1029

Context: Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potent strategy to increase glucose-dependent insulinotropic polypeptide and glucagon like peptide 1 (GLP-1) induced insulin secretion in diabetes. It is important to know whether new drugs a... Read More about The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization.